Dihydropyrrolopyridine inhibitors of ror-gamma

ABSTRACT

pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by ROR. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/455,481 filed Mar. 10, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/990,430 filed Jan. 7, 2016, now U.S. Pat. No.9,624,217, which is a continuation of U.S. patent application Ser. No.14/609,798 filed Jan. 30, 2015, now U.S. Pat. No. 9,266,886, whichclaims the benefit of U.S. Provisional Application No. 61/935,162 filedFeb. 3, 2014 and U.S. Provisional Application No. 61/970,637 filed Mar.26, 2014. The entire contents of the aforementioned applications areincorporated by reference herein.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 22, 2017, isnamed 121374-00806_SL.txt and is 636 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to novel retinoic acidreceptor-related orphan receptor gamma (“ROR

” or “ROR-gamma”) inhibitors, processes for their preparation,pharmaceutical compositions containing these inhibitors, and their usein the treatment of inflammatory, metabolic, autoimmune and otherdiseases mediated by ROR

.

BACKGROUND OF THE INVENTION

Retinoic acid receptor-related orphan receptors (RORs) are a subfamilyof transcription factors in the steroid hormone nuclear receptorsuperfamily (Jetten & Joo (2006) Adv. Dev. Biol. 2006, 16, 313-355). TheROR family consists of ROR alpha (RORα), ROR beta (RORβ) and ROR gamma(ROR

), each encoded by a separate gene (in human: RORA, RORB and RORC,respectively; in mouse: rora, rorb and rorc, respectively). RORs containfour principal domains shared by the majority of nuclear receptors: anN-terminal domain, a highly conserved DNA-binding domain (DBD)consisting of two zinc finger motifs, a hinge domain, and a ligandbinding domain (LBD). Each ROR gene generates several isoforms,differing only in their N-terminal domains. ROR

has two isoforms: ROR

1 and ROR

2 (also known as ROR

t). ROR

refers to ROR

1 and/or ROR

t. ROR

1 is expressed in a variety of tissues including thymus, muscle, kidneyand liver, but ROR

t is exclusively expressed in the cells of the immune system, has acritical role in thymopoiesis and the development of several secondarylymphoid tissues, and is a key regulator of Th17 cell differentiation(Jetten, 2009, Nucl. Recept. Signal., 7:e003, doi:10.1621/nrs.07003,Epub 2009 Apr. 3).

Th17 cells are a subset of T helper cells which preferentially producethe pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Th17cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSFand CCL20, are associated with the pathogenesis of several autoimmuneand inflammatory diseases, such as rheumatoid arthritis, systemic lupuserythematosus, multiple sclerosis, psoriasis, inflammatory boweldisease, allergy and asthma (Maddur et al., 2012, Am. J. Pathol.,181:8-18). Recent findings support a role for IL17 and Th17 cells in thepathogenesis of acne (Thiboutot et al., 2014, J. Invest. Dermatol.,134(2):307-10, doi: 10.1038/jid.2013.400; Agak et al., 2014, J. Invest.Dermatol., 134(2):366-73, doi: 10.1038/jid.2013.334, Epub 2013 Aug. 7).Th17 cells are also potent inducers of inflammation associated withendometriosis, a chronic inflammatory disease (Hirata et al., 2010,Endocrinol., 151:5468-5476; Hirata et al., 2011, Fertil Steril., July;96(1):113-7, doi: 10.1016/j.fertnstert.2011.04.060, Epub 2011 May 20).Additionally, Th17 cells have a key role in the mouse autoimmune modelsof experimental autoimmune encephalomyelitis (EAE), collagen-inducedarthritis (CIA) and adjuvant-induced arthritis (AIA) (Bedoya et al.,2013, Clin. Dev. Immunol., 2013:986789. Epub 2013 Dec. 26. Th17 cellsare activated during inflammatory and autoimmune disease processes andare responsible for recruiting other inflammatory cell types,particularly neutrophils, to mediate pathology in target tissues(Miossec & Kolls, 2012, Nature Rev., 11:763-776; Korn et al., 2009,Annu. Rev. Immunol., 27:485-517). Aberrant Th17 cell function has beenimplicated in a variety of autoimmune diseases, including multiplesclerosis and rheumatoid arthritis. Autoimmune disease is believed toarise from the disruption of the equilibrium between effector andregulatory T cells (Solt et al., 2012, ACS Chem. Biol., 7:1515-1519,Epub 2012 Jul. 9). The importance of ROR

t to Th17 cell differentiation and the pathogenic role of Th17 cells isevidenced by the fact that ROR

t-deficient mice have very few Th17 cells and have a reduction inseverity of EAE (Ivanov et al., 2006, Cell, 126:1121-1133).

Circadian rhythms are daily cycles of behavioral and physiologicalchanges that are regulated by endogenous circadian clocks. A number ofstudies have established links between nuclear receptor (including ROR

) function and expression, the circadian regulatory circuitry, and theregulation of various physiological processes (Jetten (2009) op. cit.).

Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatorydisease regulated by T lymphocytes. OSAS patients have a significantincrease in peripheral Th17 cell frequency, IL-17 and ROR

t levels (Ye et al., 2012, Mediators Inflamm., 815308, doi:10.1155/2012/815308, Epub 2012 Dec. 31).

A number of studies have provided evidence of a role of RORs in cancer.Mice deficient in the expression of ROR

exhibit a high incidence of thymic lymphomas that metastasize frequentlyto liver and spleen. High expression of Th17-associated genes (includingROR

) and high levels of Th17 cells in the tumor microenvironment has beenshown to correlate with a poor prognosis in various cancers, includinglung, gastric, breast and colon cancer (Tosolini et al., 2011, CancerRes., 71:1263-1271, doi: 10.1158/0008-5472.CAN-10-2907, Epub 2011 Feb.8; Su et al., 2014, Immunol. Res., 58:118-124, doi:10.1007/s12026-013-8483-y, Epub 2014 Jan. 9; Carmi et al., 2011, J.Immunol., 186:3462-3471, doi: 10.4049/jimmunol.1002901, Epub 2011 Feb.7; Chen et al., 2013, Histopathology, 63:225-233, doi:10.1111/his.12156, Epub 2013 Jun. 6).

ROR

has also been identified to have a regulatory role in lipid/glucosehomeostasis, and has been implicated in metabolic syndrome, obesity(Meissburger et al., 2011, EMBO Mol. Med., 3:637-651), hepatosteatosis,insulin resistance and diabetes.

Further support for the role of ROR

in the pathogenesis of inflammatory, metabolic, circadian effect,cancer, and autoimmune diseases and disorders can be found in thefollowing references: Chang et al., 2012, J. Exp. Pharmacol., 4:141-148;Jetten et al., 2013, Frontiers Endocrinol., 4:1-8; Huh & Littman, 2012,Eur. J. Immunol., 42:2232-2237; Martinez et al., 2008, Ann. N.Y. Acad.Sci., 1143:188-211; Pantelyushin et al., 2012, J. Clin. Invest.,122:2252-2256; Jetten & Ueda, 2002, Cell Death Differen., 9:1167-1171;Solt et al., 2010, Curr. Opin. Lipidol., 21:204-211.

In light of the role that ROR

plays in disease pathogenesis, inhibition of ROR

activity and Th17 cell differentiation and activity, including IL17production, will be of significant therapeutic benefit. It is thereforedesirable to prepare compounds that inhibit ROR

activity and hence have utility in the treatment of inflammatory,autoimmune, metabolic, circadian effect, cancer, and other diseasesmediated by ROR

, such as e.g., asthma, atopic dermatitis, acne, Crohn's disease,regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis,Behçet's disease, dermatomyositis, multiple sclerosis, ankylosingspondylitis, systemic lupus erythematosus, scleroderma, psoriasis,psoriatic arthritis, steroid resistant asthma and rheumatoid arthritis.

SUMMARY OF THE INVENTION

It has now been found that compounds described herein, andpharmaceutically acceptable compositions thereof, are effectiveinhibitors of ROR

(see e.g., Table 2). Such compounds include those of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,R⁴, X, L¹, n, m, Cy¹, and Cy² are as defined and described herein.

The provided compounds, and pharmaceutically acceptable compositionsthereof, are inverse agonists or antagonists of ROR

and are useful for treating a variety of diseases, disorders orconditions. Such diseases, disorders, or conditions include thosedescribed herein.

The provided compounds can be used alone (i.e., as a monotherapy) or incombination with one or more other therapeutic agent effective fortreating any of the indications described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R² and R³ are each independently hydrogen, hydroxy, monocycliccycloalkyl, monocyclic heterocyclyl, or (C₁-C₆)alkyl, wherein the(C₁-C₆)alkyl is optionally substituted with 1 to 2 groups independentlyselected from hydroxy, halo, and cyano;

R⁴ is hydrogen, (C₁-C₃)alkyl, or ═O;

X is —C(O)NH— or —NHC(O)—;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

L¹ is absent or is SO₂ or CR⁷R⁸;

Cy¹ is absent or is selected from (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, aryl,heteroaryl, heterocyclyl, and cycloalkyl, wherein the aryl, heteroaryl,heterocyclyl, and cycloalkyl are each optionally substituted with 1 to 3groups independently selected from R⁵;

Cy² is absent or is selected from (C₁-C₆)alkoxycarbonyl,phenyl(C₁-C₃)alkoxycarbonyl, halophenyl(C₁-C₃)alkoxycarbonyl, aryl,heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, whereinthe aryl, heteroaryl, monocyclic cycloalkyl, and moncyclic heterocyclylare each optionally substituted with 1 to 3 groups independentlyselected from R⁶;

R⁵ and R⁶ are each independently selected from halo, cyano, nitro,amino, hydroxy, carboxy, (C₁-C₆)alkyl, heterocyclyl,hydroxy(C₁-C₆)alkyl, CO₂H, (CH₂)₁₋₃COOH, (C₁-C₃)alkylcarbonyloxy,(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkylsulfinyl, (C₃-C₆)cycloalkylsulfinyl,(C₄-C₇)cycloalkylalkylsulfinyl, halo(C₁-C₆)alkylsulfonyl,halo(C₃-C₆)cycloalkylsulfinyl, halo(C₄-C₇)cycloalkylalkylsulfinyl,(C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl,(C₄-C₇)cycloalkylalkylsulfonyl, halo(C₁-C₆)alkylsulfonyl,halo(C₃-C₆)cycloalkylsulfonyl, halo(C₄-C₇)cycloalkylalkylsulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkyl-carbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, aryl, heteroaryl,oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, hydroxy(C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylhydroxycarbonyl, (C₁-C₆)alkylhydroxy(C₁-C₆)alkyl,(C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl,[(C₁-C₆)alkyl(C₄-C₆)heterocyclyl](C₁-C₆)alkyl, anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; and

R⁷ and R⁸ are each independently hydrogen, hydroxy, (C₁-C₃)alkyl,hydroxy(C₁-C₃)alkyl, mono(C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, CO₂H,(CH₂)₁₋₃COOH, moncyclic heterocyclyl, (C₁-C₃)alkoxycarbonyl,(C₁-C₃)alkyl(C₁-C₃)alkoxycarbonyl, halophenyl, halophenyl(C₁-C₃)alkyl,or quinolin-2(1H)one-4yl-methyl; or

R⁷ and R⁸, together with the carbon atom to which they are attached,form a 3- to 6-membered cycloalkyl or heterocyclyl.

2. Compounds and Definitions

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “alkyl”, used alone or as a part of a larger moiety such ase.g., “haloalkyl”, means a saturated monovalent straight or branchedhydrocarbon radical having, unless otherwise specified, 1-10 carbonatoms and includes, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like. “Monovalent” means attached tothe rest of the molecule at one point.

The term “haloalkyl” or “halocycloalkyl” include mono, poly, andperhaloalkyl groups where the halogens are independently selected fromfluorine, chlorine, and bromine.

The terms “cycloalkyl” and “cycloaliphatic”, used alone or as part of alarger moiety, refer to a saturated cyclic aliphatic monocyclic orbicyclic ring system, as described herein, having from, unless otherwisespecified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groupsinclude, without limitation, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, andcyclooctyl. It will be understood that when specified, optionalsubstituents on a cycloalkyl or cycloaliphatic group may be present onany substitutable position and, include, e.g., the position at which thecycloalkyl or cycloaliphatic group is attached.

The term “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic”used alone or as part of a larger moiety refer to saturated, partiallysaturated, or aromatic ring systems comprising all carbon atoms having,unless otherwise specified, a total of 3 to 10 ring members. It will beunderstood that when specified, optional substituents on a carbocycle,carbocyclyl, carbocyclo, or carbocyclic may be present on anysubstitutable position and, include, e.g., the position at which thecycloalkyl is attached.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to an aromaticcarbocyclic ring system having, unless otherwise specified, a total of 6to 10 ring members. The term “aryl” may be used interchangeably with theterm “aryl ring”, “aryl group”, “aryl moiety,” or “aryl radical”. Incertain embodiments of the present disclosure, “aryl” refers to anaromatic ring system which includes, but is not limited to, phenyl(abbreviated as “Ph”), naphthyl and the like. It will be understood thatwhen specified, optional substituents on an aryl group may be present onany substitutable position and, include, e.g., the position at which thearyl is attached.

The term “heteroaryl” used alone or as part of a larger moiety as in“heteroarylalkyl”, “heteroarylalkoxy”, or “heteroarylaminoalkyl”, refersto a 5-10-membered aromatic radical containing 1-4 heteroatoms selectedfrom N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl rings, where the radical or point of attachment is onthe heteroaromatic ring. Nonlimiting examples include indolyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, andquinoxalinyl. A heteroaryl group may be mono- or bicyclic. It will beunderstood that when specified, optional substituents on a heteroarylgroup may be present on any substitutable position and, include, e.g.,the position at which the heteroaryl is attached.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated orpartially unsaturated heterocyclic ring containing 1 to 4 heteroatomsindependently selected from N, O, and S. The terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein. Aheterocyclyl ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. Examples of suchsaturated or partially unsaturated heterocyclic radicals include,without limitation, tetrahydrofuranyl, tetrahydrothienyl,terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl,piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl,dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, and tetrahydropyrimidinyl. A heterocyclyl group maybe mono- or bicyclic. Unless otherwise specified, bicyclic heterocyclylgroups include, e.g., unsaturated heterocyclic radicals fused to anotherunsaturated heterocyclic radical or aromatic or heteroaryl ring, such asfor example, tetrahydronaphthyridine, indolinone,dihydropyrrolotriazole, imidazopyrimidine, quinolinone,dioxaspirodecane. It will also be understood that when specified,optional substituents on a heterocyclyl group may be present on anysubstitutable position and, include, e.g., the position at which theheterocyclyl is attached.

As used herein the terms “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

Certain of the disclosed compounds may exist in various stereoisomericforms. Stereoisomers are compounds that differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat contain two or more asymmetrically substituted carbon atoms. Thesymbol “*” in a structural formula represents the presence of a chiralcarbon center. “R” and “S” represent the configuration of substituentsaround one or more chiral carbon atoms. Thus, “R*” and “S*” denote therelative configurations of substituents around one or more chiral carbonatoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity,i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration. “R,” “S,”“S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurationsrelative to the core molecule.

The compounds of the invention may be prepared as individual enantiomersby either enantio-specific synthesis or resolved from anenantiomerically enriched mixture. Conventional resolution techniquesinclude forming the salt of a free base of each isomer of anenantiomeric pair using an optically active acid (followed by fractionalcrystallization and regeneration of the free base), forming the salt ofthe acid form of each enantiomer of an enantiomeric pair using anoptically active amine (followed by fractional crystallization andregeneration of the free acid), forming an ester or amide of each of theenantiomers of an enantiomeric pair using an optically pure acid, amineor alcohol (followed by chromatographic separation and removal of thechiral auxiliary), or resolving an enantiomeric mixture of either astarting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer over the weight of the enantiomer plus theweight of its optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has at least one chiralcenter, it is to be understood that the name or structure encompassesone enantiomer of compound free from the corresponding optical isomer, aracemic mixture of the compound and mixtures enriched in one enantiomerrelative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry and has at least two chiral centers, itis to be understood that the name or structure encompasses adiastereomer free of other diastereomers, a pair of diastereomers freefrom other diastereomeric pairs, mixtures of diastereomers, mixtures ofdiastereomeric pairs, mixtures of diastereomers in which onediastereomer is enriched relative to the other diastereomer(s) andmixtures of diastereomeric pairs in which one diastereomeric pair isenriched relative to the other diastereomeric pair(s).

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to nontoxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium,potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine,L-lysine, L-arginine, ammonium, ethanolamine, piperazine andtriethanolamine salts.

Pharmaceutically acceptable acidic/anionic salts include, e.g., theacetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate,citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrobromide, hydrochloride, malate, maleate,malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate,tartrate, and tosylate.

3. Description of Exemplary Compounds

In a first embodiment, the present invention provides a compound ofFormula (I),

or a pharmaceutically acceptable salt thereof, wherein the variables areas described above.

In a second embodiment, the compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (II) are as described for Formula (I).

In a third embodiment, the compound of Formula (I) is of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (III) are as described for Formula (I).

In a fourth embodiment, the compound of Formula (I) is of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (IV) are as described for Formula (I).

In a fifth embodiment, the compound of Formula (I) is of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (V) are as described for Formula (I).

In a sixth embodiment, the compound of Formula (I) is of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (VI) are as described for Formula (I).

In a seventh embodiment, the compound of Formula (I) is of Formula(VII):

or a pharmaceutically acceptable salt thereof, wherein the variables instructural Formula (VII) are as described for Formula (I).

In an eighth embodiment, R² and R³ in Formulas (I) to (VII) are eachindependently hydrogen, hydroxy, or (C₁-C₃)alkyl, wherein the remainderof the varables are as described in Formula (I).

In a ninth embodiment, Cy² in Formulas (I) to (VII) is present and isselected from aryl, heteroaryl, monocyclic cycloalkyl, and monocyclicheterocyclyl, each of which is optionally substituted with 1 to 2 groupsindependently selected from R⁶, wherein the remainder of the varablesare as described in Formula (I) or the eighth embodiment.

In a tenth embodiment, Cy² in Formulas (I) to (VII) is phenyl,pyrimidinyl, cyclohexyl, or pyridinyl, each of which are optionallysubstituted with 1 to 2 groups independently selected from R⁶, whereinthe remainder of the varables are as described in Formula (I) and theeighth or ninth embodiment.

In an eleventh embodiment, Cy¹ in Formulas (I) to (VII) is phenyl,piperidinyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl,piperazinyl, azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl,pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl,1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, orimidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with1 to 2 groups independently selected from R⁵, wherein the remainder ofthe varables are as described in Formula (I) and the eighth, ninth, ortenth embodiment.

In a twelfth embodiment, Cy¹ in Formulas (I) to (VII) is phenyl,piperidinyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl,piperazinyl, azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl,pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl,1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, orimidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with1 to 2 groups independently selected from R⁵, wherein at least one R⁵ is(C₁-C₃)alkylsulfonyl or (C₁-C₃)alkylaminosulfonyl, and wherein theremainder of the varables are as described in Formula (I) and theeighth, ninth, tenth, or eleventh embodiment.

In a thirteenth embodiment, R² in Formulas (I) to (VII) is (C₁-C₃)alkyl;n is 1 or 2; and Cy¹ is phenyl, pyridinyl, or piperidinyl, each of whichis optionally substituted with 1 to 2 groups independently selected fromR⁵, wherein at least one R⁵ is (C₁-C₃)alkylsulfonyl or(C₁-C₃)alkylaminosulfonyl, and wherein the remainder of the varables areas described in Formula (I) and the eighth, ninth, tenth, eleventh, ortwelfth embodiment.

In a fourteenth embodiment, Cy² in Formulas (I) to (VII) is cyclohexyloptionally substituted with 1 to 2 groups independently selected fromR⁶, wherein the remainder of the varables are as described in Formula(I) and the eighth, ninth, tenth, eleventh, twelfth, or thirteenthembodiment.

In a fifteenth embodiment, R⁵ is selected from halo, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, cyano, hydroxy(C₁-C₃)alkyl, (C₁-C₃)alkoxycarbonyl,(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, oxo, hydroxy,(C₁-C₃)alkylcarbonyl, hydroxy(C₁-C₃)alkylcarbonyl,(C₁-C₃)alkylhydroxycarbonyl, (C₁-C₃)alkylaminosulfonyl,(C₁-C₃)alkylaminocarbonyl, di(C₁-C₃)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, [(C₁-C₃)alkyl(C₄-C₆)heterocyclyl](C₁-C₃)alkyl,and (C₁-C₃)alkylhydroxy(C₁-C₃)alkyl; and R⁶ is selected from halo,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, cyano, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxycarbonyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkoxy,halo(C₁-C₃)alkoxy, oxo, hydroxy, aryl(C₁-C₃)alkoxycarbonyl,(C₁-C₃)alkylhydroxy(C₁-C₃)alkyl, heteroaryl, and (C₁-C₃)alkoxycarbonyl,wherein the remainder of the varables are as described in Formula (I)and the eighth, ninth, tenth, eleventh, twelfth, thirteenth, orfourteenth embodiment.

Alternatively, R⁵ is selected from halo, (C₁-C₃)alkoxy, hydroxy,(C₁-C₃)alkyl, hydroxy(C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₆)alkoxycarbonyl, di(C₁-C₃)alkylamino(C₂-C₆)alkoxy,[(C₁-C₃)alkyl(C₄-C₆)heterocyclyl](C₁-C₃)alkyl, oxo,(C₁-C₃)alkylcarbonyl, (C₁-C₃)alkylaminosulfonyl, (C₁-C₃)alkylsulfonyl,and cyano; and R⁶ is selected from halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy,halo, cyano, (C₁-C₃)alkoxycarbonyl, (C₁-C₃)alkylhydroxy(C₁-C₃)alkyl,2-methyl-2H-tetrazolyl, hydroxy(C₁-C₃)alkyl, and halo(C₁-C₃)alkoxy,wherein the remainder of the varables are as described in Formula (I)and the eighth, ninth, tenth, eleventh, twelfth, thirteenth, orfourteenth embodiment. In another alternative, R⁵ is selected from halo,cyano, (C₁-C₃)alkyl, (C₁-C₃)alkylaminosulfonyl, and(C₁-C₃)alkylsulfonyl; and R⁶ is selected from halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo, cyano, (C₁-C₃)alkoxycarbonyl,2-methyl-2H-tetrazolyl, and halo(C₁-C₃)alkoxy, wherein the remainder ofthe varables are as described in Formula (I) and the eighth, ninth,tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

In a sixteenth embodiment, Cy¹ in Formulas (I) to (VII) is

R¹⁰ is (C₁-C₃)alkyl or (C₁-C₃)alkylamino; and Z is CH or N, wherein theremainder of the varables are as described in Formula (I) and theeighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, orfifteenth embodiment.

In an seventeenth embodiment, Cy² in Formulas (I) to (VII) is

R¹² is (C₁-C₃)alkoxycarbonyl, halo, dihalo, (C₁-C₃)alkoxy, orhalo(C₁-C₃)alkyl; R¹³ is halo or halo(C₁-C₃)alkyl; and R¹⁴ is halo,cyano, halo(C₁-C₃)alkyl, halo(C₁-C₃)alkoxy, or 2-methyl-2H-tetrazolyl,wherein the remainder of the varables are as described in Formula (I)and the eighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth,or sixteenth embodiment.

In an eighteenth embodiment, R¹² to R¹⁴ are each CF₃, wherein theremainder of the varables are as described in Formula (I) and theeighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth,sixteenth, or seventeenth embodiment.

In a nineteenth embodiment, R² in Formulas (I) to (VII) is isopropyl andthe remainder of the variables are as described in Formula (I) and theeighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth,fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

In a twentieth embodiment, the compound of Formula (I) is of Formula(X):

or a pharmaceutically acceptable salt thereof, wherein L¹ is absent; Cy¹is phenyl optionally substituted with SO₂(C₁-C₃)alkyl orSO₂(C₁-C₃)alkylamino; n is 0 or 1; R⁴ is hydrogen or (C₁-C₃)alkyl; R²and R³ are each independently hydrogen or (C₁-C₆)alkyl; m is 0 or 1; andCy² is phenyl or cyclohexyl, each optionally substituted withhalo(C₁-C₃)alkyl, (C₁-C₃)alkyl, halo, or CN.

Specific examples of compounds of the invention are provided in theEXEMPLIFICATION. Pharmaceutically acceptable salts as well as theneutral forms of these compounds are included in the invention.

In certain embodiments, the present invention provides a method oftreating a patient (e.g., a human) with a disorder mediated by ROR

comprising the step of administering to the patient an effective amountof the compound with any compound described herein, or apharmaceutically acceptable salt or composition thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the present invention provides a methodof treating a subject (e.g., a human) with a disorder mediated by ROR

using a composition comprising a compound of Formula (I) and apharmaceutically acceptable carrier, adjuvant, or vehicle. In certainembodiments, the amount of compound of Formula (I) in a providedcomposition is such that it is effective as an inverse agonist orantagonist to ROR

in a biological sample or in a subject. In certain embodiments, aprovided composition is formulated for administration to a subject inneed of such composition. In some embodiments, a provided composition isformulated for oral administration to a subject.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a nontoxic carrier, adjuvant, or vehicle that does not destroythe pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this disclosure include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions described herein may be administered orally, parenterally,by inhalation spray, topically, rectally, nasally, buccally, vaginallyor via an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

Provided compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable compositions provided herein may beformulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered withoutfood. In other embodiments, pharmaceutically acceptable compositions ofthis disclosure are administered with food.

The amount of provided compounds that may be combined with carriermaterials to produce a composition in a single dosage form will varydepending upon the patient to be treated and the particular mode ofadministration.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated. The amount of a provided compound in the composition will alsodepend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of ROR

. Thus, in some embodiments, the present invention provides a method oftreating inflammatory, metabolic and autoimmune diseases or disordersmediated by ROR

, comprising administering a provided compound or composition. Moreparticularly, the compounds and compositions described herein act asinverse agonists or antagonists of ROR

.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed, i.e., therapeutic treatment.In other embodiments, treatment may be administered in the absence ofsymptoms. For example, treatment may be administered to a susceptibleindividual prior to the onset of symptoms (e.g., in light of a historyof symptoms and/or in light of genetic or other susceptibility factors),i.e., prophylactic treatment. Treatment may also be continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

Diseases and conditions treatable according to the methods of theinvention include, but are not limited to, inflammatory, metabolic andautoimmune diseases or disorders mediated by ROR

. These diseases and conditions include, for example, asthma, chronicobstructive pulmonary disease (COPD), bronchitis, allergic rhinitis,atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograftrejection, multiple sclerosis, scleroderma, arthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosingspondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto'sdisease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmuneocular disease, ulcerative colitis, Crohn's disease, regional enteritis,inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS),Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adiposetissue-associated inflammation, insulin resistance, type II diabetes,neuromyelitis optica, myasthenia gravis, age related maculardegeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis,psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease,scleritis, endometriosis, obstructive sleep apnea syndrome (OSAS),Behçet's disease, dermatomyositis, polymyocitis, graft versus hostdisease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fattyliver disease (NAFLD), sarcoidosis, primary sclerosing cholangitis,autoimmune thyroid disease, autoimmune polyendocrine syndrome type I,autoimmune polyendocrine syndrome type II, celiac disease,neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis,myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneousleishmaniasis, sinonasal polyposis, and cancer, including but notlimited to lung cancer, gastric cancer, breast cancer and colon cancer.

Also included are diseases or disorders which are implicated by theregulation of the circadian rhythm of individuals and include, e.g.,major depression, seasonal affective disorder, post-traumatic stressdisorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's diseaseand other central nervous system (CNS) disorders associated with alteredsleep and/or circadian rhythms.

In one embodiment, a human patient is treated with a compound of Formula(I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle,wherein said compound is present in an amount to treat or ameliorate oneor more of the diseases and conditions recited above. In an alternativeembodiment, the diseases and conditions treated or ameliorated by acompound of Formula (I) include, e.g., asthma, atopic dermatitis, acne,Crohn's disease, regional enteritis, ulcerative colitis, Sjögren'ssyndrome, uveitis, Behçet's disease, dermatomyositis, multiplesclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE),scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistantasthma and rheumatoid arthritis in the patient.

The invention further relates to a combination therapy for treating orameliorating a disease or a disorder described herein. In someembodiments, the combination therapy comprises administering at leastone compound represented by Structural Formula I in combination with oneor more agents for treating or ameliorating inflammatory, metabolic andautoimmune diseases or disorders mediated by ROR

. In some embodiments, the combination therapy comprises administeringat least one compound represented by Structural Formula I in combinationwith one or more agents for the treatment of diseases including asthma,chronic obstructive pulmonary disease (COPD), bronchitis, allergicrhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis,allograft rejection, multiple sclerosis, scleroderma, arthritis,rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, systemic lupus erythematosus (SLE), psoriasis,Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes,autoimmune ocular disease, ulcerative colitis, Crohn's disease, regionalenteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome(IBS), Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis,adipose tissue-associated inflammation, insulin resistance, type IIdiabetes, neuromyelitis optica, myasthenia gravis, age related maculardegeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis,psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease,scleritis, major depression, seasonal affective disorder, PTSD, bipolardisorder, autism, epilepsy, Alzheimer's, CNS disorders associated withaltered sleep and/or circadian rhythms, endometriosis, obstructive sleepapnea syndrome (OSAS), Behçet's disease, dermatomyositis, polymyocitis,graft versus host disease, primary biliary cirrhosis, liver fibrosis,non-alcoholic fatty liver disease (NAFLD), sarcoidosis, primarysclerosing cholangitis, autoimmune thyroid disease, autoimmunepolyendocrine syndrome type I, autoimmune polyendocrine syndrome typeII, celiac disease, neuromyelitis, juvenile idiopathic arthritis,systemic sclerosis, myocardial infarction, pulmonary hypertension,osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, andcancer, including but not limited to, lung cancer, gastric cancer,breast cancer and colon cancer.

The compounds according to the invention may also be used in combinationwith immunotherapies for the treatment of a disease or disorderdisclosed herein.

Combination therapy includes, e.g., co-administration of a compound ofthe invention and one or more other agents, sequential administration ofa compound of the invention and one or more other agents, administrationof a composition containing a compound of the invention and one or moreother agents, or simultaneous administration of separate compositionscontaining a compound of the invention and one or more other agents.

The invention further provides a method of treating a subject, such as ahuman, suffering from one of the abovementioned disorders or diseases.

The invention further relates to the use of provided compounds for theproduction of pharmaceutical compositions which are employed for thetreatment and/or prophylaxis and/or amelioration of the diseases anddisorders mentioned herein.

Compounds or compositions described herein may be administered using anyamount and any route of administration effective for treating orlessening the severity of one or more of the diseases and conditionsdescribed herein. The exact amount required will vary from subject tosubject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Provided compounds are preferablyformulated in unit dosage form for ease of administration and uniformityof dosage. The expression “unit dosage form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present disclosure will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this disclosure can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, provided compounds may be administered orally orparenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg andpreferably from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

The amount of both, a provided compound and additional therapeutic agent(in those compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the provided compound may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent.

The amount of additional therapeutic agent present in the compositionsof this disclosure will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Description of Synthesis

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. Many of the reactions can also becarried out under microwave (MW) conditions or using conventionalheating or utilizing other technologies such as solid phasereagents/scavengers or flow chemistry. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in the art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to a person of ordinary skill in the art in light ofthe following reaction schemes and examples. In cases where syntheticintermediates and final products contain potentially reactive functionalgroups, for example amino, hydroxy, thiol and carboxylic acid groups,that may interfere with the desired reaction, it may be advantageous toemploy protected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. In the discussion below variables have themeanings indicated above unless otherwise indicated. The abbreviationsused in these experimental details are listed below and additional onesshould be known to a person skilled in the art of synthesis. Inaddition, one can refer to the following references for suitable methodsof synthesis as described in March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, 1985, Greene and Wuts, Protective Groups inOrganic Synthesis, 2^(nd) edition, John Wiley & Sons, 1991, and RichardLarock, Comprehensive Organic Transformations, 4^(th) edition, VCHpublishers Inc., 1989.

Generally, reagents in the reaction schemes are used in equimolaramounts; however, in certain cases it may be desirable to use an excessof one reagent to drive a reaction to completion. This is especially thecase when the excess reagent can be readily removed by evaporation orextraction. Bases employed to neutralize HCl in reaction mixtures aregenerally used in slight to substantial excess (1.05-5 equivalents).

Where NMR data are presented, spectra were obtained on a Varian 400 (400MHz) or 300 (300 MHz) and are reported as ppm downfield fromtetramethylsilane with number of proton, multiplicities and couplingconstants indicated parenthetically along with reference to deuteratedsolvent.

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

Abbreviation Meaning ACN, MeCN, CH₃CN acetonitrile AIBNazobisisobutyronitrile aq aqueous Boc tert-butoxycarbonyl ort-butoxycarbonyl brine saturated aqueous NaCl Cbz benzyloxy carbonylCeCl₃ ceric chloride Cs₂CO₃ cesium carbonate CuI cuprous iodide DCM orCH₂Cl₂ methylene chloride DIEA diisopropyl ethyl amine DMF dimethylformamide DMS/Me₂S dimethyl sulfide DMSO dimethyl sulfoxide EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiiimide hydrochloride EtI ethyliodide Et ethyl Et₂O ethyl ether Et₃SiH triethylsilane Et₃Ntriethylamine EtOAc, EA, AcOEt ethyl acetate EtOH ethanol FeCl₃ ferricchloride h, hr hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate HBTUO-benzotriazole-1-yl-N,N,N′,N′- tetramethyluronium-hexafluorophosphateHCl hydrochloric acid H₂O water H₂O₂ hydrogen peroxide HPLC highperformance liquid chromatography i-BuOCOCl iso-butoxycarbonyl chlorideICl iodochloride K₂CO₃ potassium carbonate K₃PO₄ tripotassium phosphateLC-MS liquid chromatography-mass spectrometry LDA lithiumdiiisopropylamide LiCl lithium chloride LiOH lithium hydroxide MCPBA,m-CPBA meta-chloroperoxybenzoic acid MeOH methanol MeI methyl iodide Memethyl mg milligram MgSO₄ magnesium sulfate (anhydrous) min minute(s) mLmilliliters mmol millimoles mp, m.p. melting point MS mass spectrometryMW, uwave microwave NaBH₄ sodium borohydride NaBH₃CN sodiumcyanoborohydride NaH sodium hydride NaHCO₃ sodium bicarbonate NaOHsodium hydroxide NaOMe sodium methoxide Na₂S₂O₃ sodium thiosulfateNa₂S₂O₅ sodium dithionate Na₂SO₄ sodium sulfate NH₄OH ammonium hydroxide(NH₄)₂CO₃ ammonium carbonate NH₄Cl ammonium chloride Na₂CO₃ sodiumcarbonate NaHCO₃ sodium bicarbonate NaH sodium hydride NBSN-bromosuccinimide n-BuLi n-butyllithium NMM N-methyl-morpholine NMPN-methyl-pyrrolidin-2-one OTf trifluoromethanesulfonate OTs tosylatePdCl₂dppf [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(ii)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether rtroom temperature sat. saturated SFC supercritical fluid chromatographyt-BuOK potassium tert butoxide t-BuLi tert butyl lithium t-BuOOH tertbutyl peroxide TBAF tetrabutylammonium fluoride TFA trifluoroacetic acidTHF tetrahydrofuran TLC thin layer chromatography Ti(OEt)₄ titaniumtetra ethoxide Zn zinc Zn(CN)₂ zinc cyanide

Compounds according to Formula (I), can be prepared by reacting anintermediate compound of Formula (500) with an alkyl or aryl halide,according to reaction Scheme 1, a reaction that is performed in a polaraprotic solvent, such as, for example, acetonitrile, in the presence ofa suitable base, such as, for example, N,N-diisopropylethylamine orpotassium carbonate. Alternatively, the final compounds according toFormula (I), can be prepared by reacting an intermediate compound ofFormula (500) with an aldehyde or ketone, according to reaction Scheme1, following art-known reductive amination procedure, in the typicalsolvent, such as, for example, dichloroethane, dichloromethane, ormethanol; in the presence of suitable reducing reagent, such as sodiumcyanoborohydride or sodium triacetoxyborohydride. In reaction Scheme 1,all variables are defined as in Formula (I) and G¹ is a leaving group,such as for example, bromide, chloride, mesylate (methanesulfonate),tosylate (p-toluenesulfonate), or iodide.

Intermediate compound of Formula (500) can be can be prepared bydeprotecting an intermediate compound of Formula (501), wherein Pg is asuitable nitrogen protecting group (Greene and Wuts, Protective Groupsin Organic Synthesis, 2^(nd) edition, John Wiley & Sons, 1991), e.g.,Pg=tert-butoxycarbonyl, removed with trifluoroacetic acid according toScheme 2. In reaction Scheme 2, all variables are defined as in Formula(I).

Intermediate compound of Formula (502), wherein X is C(═O)NH, can beprepared from a carboxylic acid (504) and an amine (503), according toScheme 3. The reaction is conveniently carried out in the presence of anactivating reagent, for example,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example,N,N-dimethylformamide or dichloromethane, optionally in the presence ofa base, e.g., N,N-diisopropylethylamine or triethylamine, at atemperature, for example in the range from 0 to 60° C.

Intermediate compound of Formula (505), wherein X is NHC═O, can beprepared from an intermediate compound of Formula (506) and an amide(507), according to Scheme 4. The reaction is carried out in thepresence of a catalyst, for example,tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃), in an organicsolvent, for example, dioxane or tert-butanol, in the presence of anadditive, e.g., potassium phosphate, at a temperature, for example, inthe range from 80 to 150° C.

Preparation of Intermediates

As a representative example, intermediate compound of Formula (504)wherein R⁴ is H, R² is isopropyl, R³ is H and Pg is tert-butoxycarbonyl,can be prepared by following the reaction steps shown in Scheme 5. Anintermediate compound of Formula (504) with variables R⁴, R² and R³ canbe prepared readily according to Scheme 5, or modifications thereof,using readily available starting materials and reagents.

To a stirred solution of compound Boc-Val-OH (3.11 g, 14.3 mmol) in THF(40 mL) at rt was added 1,1′-carbonyldiimidazole (3.48 g, 21.5 mmol).The mixture was stirred at rt for 1 h, then magnesium chloride (1.36 g,14.3 mmol) and ethyl potassium malonate (2.44 g, 14.3 mmol) were addedsuccessively. The mixture was then heated to 50° C. and stirred for 15h. The mixture was cooled to rt and quenched with 1 N HCl (100 mL). Theaqueous phase was extracted with EtOAc (3×100 mL), then the combinedorganic layer was washed with brine (50 mL). The organic layer was driedover anhydrous MgSO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography (eluting with 5%EtOAc in hexanes) to afford ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (3.53 g, 86%yield) as a yellow oil. LC-MS t_(R)=0.91 min in 1 min chromatography, MS(ESI) m/z 288.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 5.08 (d, J=8.4 Hz,1H), 4.33 (dd, J=4.4 Hz, 8.8 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.54 (s,2H), 2.27-2.17 (m, 1H), 1.44 (s, 9H), 1.27 (t, J=7.2 Hz, 3H), 1.01 (d,J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H).

To a mixture of ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (9.68 g, 33.7mmol) from above in THF (100 mL) at 0° C. was added potassiumtert-butoxide (3.78 g, 35.4 mmol). The mixture was warmed to rt andstirred for 45 min, at which point 1,4-diazabicyclo[2.2.2]octane (3.78g, 33.7 mmol) and 2-chloro-1,3-bis(dimethylamino)trimethiniumhexaflurophosphate (15.5 g, 50.5 mmol) were added successively. Themixture was heated to 45° C. and stirred for 3 h, at which pointammonium acetate (5.19 g, 67.4 mmol) was added. The mixture was thenheated to reflux and stirred for 15 h. It was then cooled to rt andconcentrated under reduced pressure. The residue was dry-loaded onto asilica gel column and purified (eluting with 5% EtOAc in hexanes,gradient to 15%) to yield 6.09 g of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate(51%). LC-MS t_(R)=1.14 min in 1 min chromatography, MS (ESI) m/z 357.3[M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.18 (d,J=2.8 Hz, 1H), 5.71 (d, J=9.6 Hz, 1H), 5.62 (dd, J=5.2 Hz, 9.6 Hz, 1H),4.42 (q, J=7.2 Hz, 2H), 2.08-2.00 (m, 1H), 1.42 (s, 9H), 1.42 (t, J=7.2Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H).

To a stirred solution of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate(6.09 g, 17.1 mmol) at 0° C. in EtOH (70 mL) was added sodiumborohydride (1.30 g, 34.1 mmol). Calcium chloride (1.89 g, 17.1 mmol)was added portionwise while maintaining the temperature between 0° C.and 5° C. The resulting mixture was stirred at 0° C. for 90 min, thenquenched slowly at 0° C. with saturated aqueous ammonium chloridesolution (100 mL). The aqueous phase was extracted with EtOAc (3×100mL), then the combined organic layer was washed with brine (50 mL),dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. Crude tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamatewas carried forward without any purification. LC-MS t_(R)=0.94 min in 1min chromatography, MS (ESI) m/z 315.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):δ 8.46 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.8 Hz, 1H), 5.34 (d, J=9.2 Hz,1H), 4.99 (dd, J=2.0 Hz, 8.4 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 4.41 (dd,J=10.0 Hz, 12.4 Hz, 1H), 4.33 (d, J=10.0 Hz, 1H), 2.18-2.12 (m, 1H),1.36 (s, 9H), 1.10 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H).

To a solution of tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamate(5.33 g, 16.9 mmol) in CH₂Cl₂ (70 mL) at 0° C. was added triethylamine(3.54 mL, 25.4 mmol) and methanesulfonyl chloride (1.44 mL, 18.6 mmol).The mixture was warmed to rt and stirred for 3 h, at which point it wasquenched with saturated aqueous sodium bicarbonate solution (100 mL).The aqueous phase was extracted with ethyl acetate (3×100 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue (a 3:1 mixture of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate)was carried forward without any purification. LC-MS t_(R)=1.01 min in 1min chromatography, MS (ESI) m/z 393.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):δ 8.53 (d, J=2.4 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 5.44 (d, J=12.4 Hz,1H), 5.37 (d, J=12.8 Hz, 1H), 5.31 (d, J=8.4 Hz, 1H), 4.59 (t, J=9.2 Hz,1H), 3.13 (s, 3H), 2.13-2.04 (m, 1H), 1.36 (s, 9H), 1.03 (d, J=6.8 Hz,3H), 0.77 (d, J=6.8 Hz, 3H). Characterization data from a purifiedsample of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate.

To a solution of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate(3:1 mixture, 6.39 g, 16.9 mmol) in THF (75 mL) at 0° C. was addedsodium hydride (60% dispersion in mineral oil, 811 mg, 20.3 mmol). Themixture was warmed to rt and stirred for 15 h, at which point it wasquenched with saturated aqueous ammonium chloride solution (100 mL). Theaqueous phase was extracted with ethyl acetate (3×100 mL). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (eluting with 5% EtOAc in hexanes,gradient to 10%) to give tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(4.31 g, 85% yield over 3 steps) as a yellow oil. LC-MS t_(R)=1.12 minin 1 min chromatography, MS (ESI) m/z 297.3 [M+H]⁺. ¹H NMR (CDCl₃, 400MHz, mixture of rotamers): δ 8.43 (s, 1H), 7.56 (s, 0.6H), 7.50 (s,0.4H), 4.96 (s, 0.4H), 4.87 (s, 0.6H), 4.86 (d, J=16.0 Hz, 0.6H), 4.74(d, J=15.6 Hz, 0.4H), 4.52 (d, J=12.0 Hz, 0.4H), 4.49 (d, J=15.2 Hz,0.6H), 2.60-2.51 (m, 0.4H), 2.40-2.36 (m, 0.6H), 1.49 (s, 9H), 1.08 (d,J=7.2 Hz, 1.2H), 0.99 (d, J=7.2 Hz, 1.8H), 0.78 (d, J=6.8 Hz, 1.8H),0.72 (d, J=6.8 Hz, 1.2H).

Potassium carbonate (758 mg, 5.49 mmol) and 4 Å molecular sieves (250mg) were placed in a 50 mL round-bottom flask which was then flamedried. Palladium (II) acetate (32.8 mg, 146 μmol) and1,3-bis(dicyclohexylphosphonium)propane bis (tetrafluoroborate) (179 mg,292 μmol) were added to the flask, which was then sealed with a septum.Tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(1.09 g, 3.66 mmol) was dissolved in DMF (12 mL) and added to the flask,followed by 1-butanol (3.34 mL, 36.6 mmol). The flask was then evacuatedand backfilled with CO three times, with the final time under a balloonof 1 atm of CO. The flask was heated to 100° C. and stirred for 6 h. Themixture was then cooled to rt and quenched with 1 N NaOH (25 mL). Themixture was stirred for 30 min, at which point isopropyl acetate (50 mL)was added. The phases were separated, then the organic phase wasextracted with 1 N NaOH (2×50 mL), then the combined aqueous layer wasacidified to pH=2 with concentrated HCl. The aqueous layer was thenextracted with EtOAc (3×25 mL), then the combined organic layer wasdried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The crude residue(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid was carried forward without any purification.

Alternative two-step procedure for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid: To a solution of tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(158 mg, 532 μmol) in MeOH (2.5 mL) in a MW vial was added molybdenumhexacarbonyl (155 mg, 587 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene(279 μL, 1.86 mmol). The mixture was degassed with N₂ for 15 min, atwhich pointtrans-bis(acetate)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(25.0 mg, 26.6 μmol) and tri-tert-butylphosphonium tetrafluoroborate(30.9 mg, 107 μmol) were added. The vial was sealed and heated in the MWat 160° C. for 20 min After cooling to rt, the mixture was filteredthrough Celite with MeOH and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 10%EtOAc in hexanes, gradient to 25%) to afford 70.7 mg of 6-(tert-butyl)3-methyl(S)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-3,6-dicarboxylate(41% yield). LC-MS t_(R)=1.04 min in 1 min chromatography, MS (ESI) m/z321.4 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, mixture of rotamers): δ 9.10 (s,1H), 8.17 (s, 0.6H), 8.13 (s, 0.4H), 5.05 (s, 0.4H), 4.95 (s, 0.6H),4.90 (d, J=15.6 Hz, 0.6H), 4.79 (d, J=15.6 Hz, 0.4H), 4.58 (d, J=11.2Hz, 0.4H), 4.54 (d, J=15.6 Hz, 0.6H), 3.96 (s, 3H), 2.62-2.53 (m, 0.4H),2.45-2.38 (m, 0.6H), 1.52 (s, 9H), 1.09 (d, J=6.8 Hz, 1.2H), 0.99 (d,J=7.2 Hz, 1.8H), 0.79 (d, J=6.8 Hz, 1.8H), 0.72 (d, J=6.8 Hz, 1.2H).

To a solution of 6-(tert-butyl) 3-methyl(S)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-3,6-dicarboxylate(70.7 mg, 221 μmol) in MeOH was added potassium hydroxide (5.9 Msolution in H₂O, 187 μL, 1.10 mmoL). The mixture was stirred at 40° C.for 1 h, at which point it was cooled to rt and partitioned betweendiethyl ether (25 mL) and 1 N NaOH (25 mL). The organic phase wasextracted with 1 N NaOH (2×25 mL), then the combined aqueous layer wasacidified to pH=2 with concentrated HCl. The aqueous layer was thenextracted with EtOAc (3×25 mL), then the combined organic layer wasdried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The crude residue(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid was carried forward without any purification. LC-MS t_(R)=0.93 minin 1 min chromatography, MS (ESI) m/z 307.4 [M+H]⁺. ¹H NMR (CDCl₃, 400MHz, mixture of rotamers): δ 9.19 (s, 1H), 8.23 (s, 0.6H), 8.19 (s,0.4H), 5.09 (s, 0.4H), 4.99 (s, 0.6H), 4.94 (d, J=15.6 Hz, 0.6H), 4.82(d, J=14.4 Hz, 0.4H), 4.60 (d, J=8.8 Hz, 0.4H), 4.57 (d, J=16.0 Hz,0.6H), 2.65-2.57 (m, 0.4H), 2.49-2.41 (m, 0.6H), 1.53 (s, 9H), 1.10 (d,J=6.4 Hz, 1.2H), 1.00 (d, J=6.8 Hz, 1.8H), 0.82 (d, J=6.8 Hz, 1.8H),0.75 (d, J=6.8 Hz, 1.2H).

(4-(ethylsulfonyl)phenyl)methanamine was prepared following thesynthetic route shown in Scheme 6.

A mixture of 4-methylbenzenethiol (100 g, 0.8 mol) in acetone (1 L) wasadded iodoethane (190 g, 1.2 mol) and potassium carbonate (220 g, 1.6mol). The mixture was stirred at 60° C. overnight. The mixture wasfiltered and the filtrate was concentrated under reduced pressure toafford crude ethyl(p-tolyl)sulfane (120 g, 99%) as a yellow solid, whichwas used for the next step without further purification.

To a solution of crude ethyl(p-tolyl)sulfane (35 g, 0.23 mol) in CH₂Cl₂(1.5 L) was added m-chloroperoxybenzoic acid (101 g, 0.59 mol) at 0° C.The mixture was stirred at rt overnight. The mixture was filtered. Thefiltrate was added to saturated aqueous Na₂SO₃ (500 mL) slowly and thenstirred for 0.5 h. After partitioning, the organic layer was washed withsaturated aqueous NaHCO₃ (500 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to afford crude1-(ethylsulfonyl)-4-methylbenzene (42.3 g, 100%) as a pale yellow solid,which was used for the next step without further purification.

To a solution of 1-(ethylsulfonyl)-4-methylbenzene (5 g, 25.7 mmol) inCCl₄ (30 mL) was added N-bromosuccinimide (5.54 g, 30.8 mmol) andazobisisobutyronitrile (0.46 g, 2.57 mmol). The mixture was stirred at80° C. overnight. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was added to water (50mL) and extracted with EtOAc (3×30 mL). The combined organic layers werewashed with water (2×40 mL) and brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford crude1-(bromomethyl)-4-(ethylsulfonyl)benzene (6.62 g, 98%) as a yellowsolid, which was used for the next step without further purification.

To a solution of 1-(bromomethyl)-4-(ethylsulfonyl)benzene (6.62 g, 25.2mmol) in MeOH (30 mL) was added 28% aqueous ammonium hydroxide solution(30 mL). The mixture was stirred at rt overnight. The mixture was thenconcentrated under reduced pressure. The residue was purified by basicpreparative HPLC separation to afford(4-(ethylsulfonyl)phenyl)methanamine (1.5 g, 30%) as a yellow solid.LC-MS t_(R)=1.747 min in 0-30CD_3 min chromatography (Durashell C18,2.1*30 mm, 3 um), MS (ESI) m/z 200.0 [M+H]⁺ and 399.0 [2M+H]⁺. ¹H NMR(CDCl₃, 400 MHz): δ 7.85 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 3.98(s, 2H), 3.10 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H). PreparativeBasic HPLC Method mobile phase A: water with 0.05% NH₃H₂O solution;mobile phase B: MeCN; flow rate: 30 ml/min; detection: UV 220 nm/254 nm;column: Synergi 200 mm×25 mm×5 μm; column temperature: 30° C.

Time in min % A % B 0.0 63 37 8.0 33 67 8.10 0 100 10.0 0 100 10.1 70 3012 70 30

(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidewas prepared following the synthetic route shown in Scheme 7.

To a solution of(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid (83.3 mg, 281 μmol) and (4-(ethylsulfonyl)phenyl)methanamine (67.1mg, 337 μmol) in DMF (2 mL) at rt was added HATU (160 mg, 421 μmol) anddiisopropylethylamine (97.8 μL, 561 μmol). The mixture was stirred at rtfor 15 h, at which point it was quenched with saturated aqueous ammoniumchloride solution (15 mL). EtOAc (25 mL) was added, then the phases wereseparated. The organic layer was washed with brine (15 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 50%EtOAc in hexanes, gradient to 100%) to afford 98.0 mg tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,(15), (77%). LC-MS t_(R)=0.92 min in 1 min chromatography, MS (ESI) m/z488.5 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz, mixture of rotamers): δ 8.94 (d,J=2.0 Hz, 1H), 8.16 (d, J=12.0 Hz, 1H), 7.89 (dd, J=2.0 Hz, 8.4 Hz, 2H),7.64 (d, J=8.8 Hz, 2H), 4.96 (m, 1H), 4.83 (m, 1H), 4.70 (s, 2H), 4.59(m, 1H), 3.20 (q, J=7.2 Hz, 2H), 2.56-2.42 (m, 1H), 1.48 (s, 9H), 1.20(t, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 1.5H), 1.02 (d, J=6.8 Hz, 1.5H),0.80 (d, J=6.8 Hz, 1.5H), 0.74 (d, J=6.8 Hz, 1.5H).

To a solution of tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(98.0 mg, 201 μmol) in CH₂Cl₂ (4 mL) at rt was added trifluoroaceticacid (1.5 mL). The solution was stirred for 30 min, then it was cooledto 0° C. and quenched carefully with saturated sodium bicarbonatesolution (20 mL). The mixture was warmed to rt, then 1 N NaOH (10 mL)and brine (10 mL) were added. The aqueous phase was extracted withCH₂Cl₂ (5×25 mL), then the combined organic layer was dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Thecrude(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidewas carried forward without any purification. LC-MS t_(R)=0.49 min in 1min chromatography, MS (ESI) m/z 388.4 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):δ 9.06 (t, J=0.8 Hz, 1H), 8.23 (t, J=0.8 Hz, 1H), 7.89 (dd, J=1.6 Hz,8.4 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 4.85 (d, J=4.0 Hz, 1H), 4.73 (s,2H), 4.71 (s, 2H), 3.20 (q, J=7.6 Hz, 2H), 2.59-2.54 (m, 1H), 1.21 (t,J=7.6 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 1.07 (d, J=7.2 Hz, 3H).

(5-(ethylsulfonyl)pyridin-2-yl)methanamine was prepared following thesynthetic route shown in Scheme 8.

To a flame dried flask equipped with a stir bar was added tert-butyl((5-bromopyridin-2-yl)methyl)carbamate (2.92 g, 10.2 mmol), ethanesulfinic acid sodium salt (2.36 g, 20.3 mmol), L-proline (234 mg, 2.03mmol), copper (I) iodide (194 mg, 1.02 mmol) and sodium hydroxide (81.3mg, 2.03 mmol). The flask was purged with N₂, then DMSO (35 mL) wasadded. The reaction mixture was heated to 110° C. and stirred for 15 h.The flask was then cooled to rt and the mixture was partitioned betweenEtOAc (150 mL) and saturated aqueous ammonium chloride (150 mL). Theorganic phase was separated, washed with brine (50 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 35%EtOAc in hexanes, gradient to 60%) to afford 1.81 g tert-butyl((5-bromopyridin-2-yl)methyl)carbamate (59%). LC-MS t_(R)=0.74 min in 1min chromatography, MS (ESI) m/z 301.4 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz):δ 9.02 (dd, J=0.8 Hz, 2.0 Hz, 1H), 8.15 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.49(dd, J=0.8 Hz, 8.4 Hz, 1H), 5.49 (broad s, 1H), 4.55 (d, J=7.0 Hz, 2H),3.15 (q, J=7.2 Hz, 2H), 1.47 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).

To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (1.81g, 6.03 mmol) in MeOH (40 mL) at 0° C. was added acetyl chloride (4.30mL, 60.3 mmol) dropwise over 5 min. The solution was allowed to warm tort and was stirred for 3 h. The mixture was concentrated under reducedpressure to yield 1.64 g (5-(ethylsulfonyl)pyridin-2-yl)methanaminebishydrochloride (˜100%). LC-MS t_(R)=0.25 min in 1 min chromatography,MS (ESI) m/z 201.2 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.09 (d, J=1.2 Hz,1H), 8.35 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 4.45 (s,2H), 3.31 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).

Tert-butyl(S)-3-(((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(46): Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,using (5-(ethylsulfonyl)pyridin-2-yl)methanamine as a starting material.LC-MS t_(R)=0.86 min in 1 min chromatography, MS (ESI) m/z 489.4 [M+H]⁺.¹H NMR (CDCl₃, 400 MHz, mixture of rotamers): δ 9.06 (s, 1H), 8.96 (s,1H), 8.20 (dd, J=2.0 Hz, 8.4 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.56 (d,J=8.0 Hz, 1H), 7.52 (s, 1H), 4.99 (m, 2H), 4.90 (m, 2H), 4.80 (d, J=15.2Hz, 1H), 4.51 (m, 1H), 3.17 (q, J=7.6 Hz, 2H), 2.63-2.54 (m, 0.5H),2.48-2.39 (m, 0.5H), 1.52 (s, 9H), 1.33 (t, J=7.6 Hz, 3H), 1.10 (d,J=7.2 Hz, 1.5H), 1.01 (d, J=6.8 Hz, 1.5H), 0.78 (d, J=6.8 Hz, 1.5H),0.73 (d, J=7.2 Hz, 1.5H).

(S)—N-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide:Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using tert-butyl(S)-3-(((5-(ethylsulfonyl)pyridin-2-yl)methyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material. LC-MS t_(R)=0.48 min in 1 min chromatography, MS(ESI) m/z 389.3 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz): δ 9.06 (dd, J=0.8 Hz,2.0 Hz, 1H), 8.93 (t, J=0.8 Hz, 1H), 8.19 (dd, J=2.0 Hz, 8.4 Hz, 1H),8.01 (t, J=0.8 Hz, 1H), 7.56 (dd, J=0.8 Hz, 8.0 Hz, 1H), 7.52 (s, 1H),4.89 (d, J=5.2 Hz, 2H), 4.35 (dd, J=1.2 Hz, 4.0 Hz, 1H), 4.32 (d, J=0.8Hz, 2H), 3.17 (q, J=7.6 Hz, 2H), 2.34-2.26 (m, 1H), 1.33 (t, J=7.6 Hz,3H), 1.09 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H).

2-(4-(ethylsulfonyl)phenyl)acetamide was prepared following thesynthetic route shown in Scheme 9.

A solution of sodium nitrite (18.4 g, 0.267 mol) in water (133 mL) wasadded dropwise to a suspension of 2-(4-aminophenyl)acetic acid (40.3 g,0.267 mol) in water (133 mL) and conc. HCl (54 mL, 0.65 mol) at 0° C.After addition, the reaction mixture was stirred at the same temperaturefor 45 min. The solution of the cold diazonium salt was then addeddropwise to a mixture of potassium ethyl xanthate (49.3 g, 0.31 mol),water (80 mL) and aqueous sodium carbonate solution (200 mL, 2 M) at rt.After addition, the mixture was allowed to warm to 45° C. and stirred atthis temperature until gas evolution ceased (about 3 h to overnight).The mixture was cooled to rt and adjusted to pH=1 with conc. HCl. Theaqueous layer was extracted with ethyl acetate (3×300 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford crude2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid (50 g, 73%) as a darkred liquid, which was used for next step directly without furtherpurification. ¹H NMR (purified by pre-TLC, CDCl₃ 300 MHz): δ 7.40 (d,J=7.5 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 4.54 (q, J=6.9 Hz, 2H), 3.63 (s,2H), 1.26 (t, J=6.9 Hz, 3H).

To a solution of 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid(50.0 g, crude, 0.195 mol) in EtOH (180 mL) was added a solution of KOH(40.5 g, 0.724 mol) in water (180 mL). The mixture was stirred at refluxovernight. The mixture was concentrated under reduced pressure to removeEtOH. The aqueous phase was adjusted to pH=1˜2 with conc. HCl. Theaqueous phase was then extracted with ethyl acetate (3×200 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford crude2-(4-mercaptophenyl)acetic acid (32.0 g, 98%) as a gray solid, which wasused for next step directly without further purification. ¹H NMR(purified by pre-TLC, CD₃OD, 400 MHz): 7.23 (d, J=8.4 Hz, 2H), 7.15 (d,J=8.0 Hz, 2H), 3.54 (s, 2H).

To a solution of 2-(4-mercaptophenyl)acetic acid (32 g, crude, 0.19 mol)in dry DMF (300 mL) was added potassium carbonate (105 g, 0.76 mol) andiodoethane (118 g, 0.76 mol). The reaction mixture was stirred at rtovernight. Ethyl acetate (800 mL) and water (600 mL) were added to themixture. After partitioning, the aqueous layer was extracted with ethylacetate (3×500 mL). The combined organic layers were washed with brine(2×800 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluting with 30:1 petroleum ether:ethyl acetate) to giveethyl 2-(4-(ethylthio)phenyl)acetate (15.3 g, 36%) as a yellow oil.LC-MS t_(R)=0.881 min in 5-95AB_1.5 min chromatography (Welch XtimateC18, 2.1*30 mm, 3 urn), MS (ESI) m/z 224.8 [M+H]⁺. ¹H NMR (CDCl₃ 300MHz): δ 7.02 (d, J=8.1 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 3.89 (q, J=7.2Hz, 2H), 3.31 (s, 2H), 2.67 (q, J=7.5 Hz, 2H), 1.07-0.97 (m, 6H).

To a solution of ethyl 2-(4-(ethylthio)phenyl)acetate (7.8 g, 35 mmol)in CH₂Cl₂ (100 mL) was added m-chloroperoxybenzoic acid (21 g, 123 mmol)in portions at 0° C. The reaction mixture was stirred for 16 h at rt.The reaction mixture was filtered. CH₂Cl₂ (200 mL) was added to thefiltrate and then the mixture was quenched with saturated aqueous Na₂SO₃solution (200 mL). After partitioning, the organic layer was washed withsaturated aqueous Na₂SO₃ solution (200 mL) and then saturated aqueousNa₂CO₃ solution (300 mL). The combined aqueous layers were extractedwith CH₂Cl₂ (3×400 mL). The combined organic layers were washed withbrine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by column on silica gel(eluting with 15% EtOAc in petroleum ether, gradient to 25%) to affordethyl 2-(4-(ethylsulfonyl)phenyl)acetate (7.0 g, 78%) as a white solid.LC-MS t_(R)=0.807 min in 5-95AB_2 min chromatography (Welch Xtimate C18,2.1*30 mm, 3 urn), MS (ESI) m/z 256.8 [M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ7.87 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 4.18 (q, J=6.8 Hz, 2H),3.72 (s, 2H), 3.11 (q, J=7.6 Hz, 2H), 1.30-1.25 (m, 6H).

To a solution of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (10.0 g, 39mmol) in EtOH (100 mL) was added a solution of NaOH (5.7 g, 142.5 mmol)in water (100 mL). The reaction mixture was stirred at rt for 16 h. EtOHwas removed under reduced pressure. The aqueous layer was adjusted topH=1 with 6 N aq. HCl and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive the desired product 2-(4-(ethylsulfonyl)phenyl)acetic acid (7.3 g,82%) as a white solid. LC-MS t_(R)=0.573 min in 5-95AB_1.5 minchromatography (Welch Xtimate C18, 2.1*30 mm, 3 urn), MS (ESI) m/z 228.8[M+H]⁺. ¹H NMR (CDCl₃ 400 MHz): δ 7.88 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 3.77 (s, 2H), 3.12 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).

To a mixture of 2-(4-(ethylsulfonyl)phenyl)acetic acid (3 g, 13.2 mmol),Et₃N (4.0 g, 39.6 mmol) and HATU (5.93 g, 15.6 mmol) in anhydrous CH₂Cl₂(100 mL) was added NH₄Cl (1.54 g, 26.4 mmol). The resulting mixture wasstirred at rt overnight. The mixture was diluted with CH₂Cl₂ (100 mL)and washed with water (3×80 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (elutingwith 50% EtOAc in petroleum ether, gradient to 100%) to afford crude2-(4-(ethylsulfonyl)phenyl)acetamide. The crude product was added topetroleum ether/ethyl acetate (20 mL, 1/1), then the mixture was stirredfor 0.5 h. The mixture was filtered and the filter cake was dried undervacuum to give 2-(4-(ethylsulfonyl)phenyl)acetamide (1.5 g, 50%) as awhite solid. LC-MS t_(R)=0.900 min in 0-30AB_2 min chromatography (WelchXtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 269.0 [M+H+CH₃CN]⁺. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.80 (d, J=8.0 Hz, 2H), 7.58 (broad s, 1H), 7.51(d, J=8.0 Hz, 2H), 7.00 (broad s, 1H), 3.50 (s, 2H), 3.25 (q, J=7.2 Hz,2H), 1.08 (t, J=7.2 Hz, 3H).

Tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate:To a flame-dried vial equipped with a stir bar was added tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(74.7 mg, 252 μmol), 2-(4-(ethylsulfonyl)phenyl)acetamide (68.6 mg, 302μmol), and potassium phosphate (64.1 mg, 302 μmol). Tert-butanol (1.5mL) was added, then the mixture was degassed with N₂ for 15 min.Tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 252 nmol) and2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(4.9 mg, 10.1 μmol) were added to the mixture, then the vial was sealedand heated at 110° C. for 15 h. The mixture was cooled to rt, thenpartitioned between EtOAc (15 mL) and brine (15 mL). The organic phasewas separated, dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (eluting with 10% EtOAc in hexanes, gradient to 100%) toafford 70.2 mg of Tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(57%). LC-MS t_(R)=0.90 min in 1 min chromatography, MS (ESI) m/z 488.5[M+H]⁺. ¹H NMR (CD₃OD, 400 MHz, mixture of rotamers): δ 8.58 (s, 0.5H),8.54 (s, 0.5H), 8.10 (s, 1H), 7.89 (dd, J=8.0 Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 4.77 (d, J=15.6 Hz, 1H), 4.51 (m, 2H), 3.87 (s, 2H), 3.21 (q,J=7.2 Hz, 2H), 2.46-2.37 (m, 1H), 1.52 (s, 9H), 1.22 (t, J=7.6 Hz, 3H),1.02 (d, J=6.8 Hz, 1.5H), 0.99 (d, J=6.4 Hz, 1.5H), 0.77 (d, J=7.2 Hz,1.5H), 0.73 (d, J=6.8 Hz, 1.5H).

(S)-2-(4-(ethylsulfonyl)phenyl)-N-(7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)acetamide:Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material. LC-MS t_(R)=0.50 min in 1 min chromatography, MS(ESI) m/z 388.3 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.02 (s, 1H), 8.48(s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.84 (m, 2H), 7.66 (d, J=8.0 Hz, 1H),7.56 (d, J=8.4 Hz, 1H), 4.78 (m, 2H), 3.98 (s, 1H), 3.81 (s, 1H), 3.70(s, 1H), 3.20 (q, J=7.6 Hz, 2H), 2.65-2.57 (m, 1H), 1.21 (t, J=7.6 Hz,3H), 1.21 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).

Preparation of Compounds of Formula I

Compounds of Formula (I) were prepared according to the generalprocedures outlined below.

General Procedure A:(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(1)

(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(11.3 mg, 29.2 μmol), 4-(trifluoromethyl)benzyl bromide (10.5 mg, 43.9μmol), and potassium carbonate (8.1 mg, 58.6 μmol) were stirred togetherin CH₃CN (1 mL) at rt for 2 h. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution (5 mL) and extracted withEtOAc (10 mL). The organic phase was separated, washed with brine (5mL), dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith 50% EtOAc in hexanes, gradient to 100%), then further purified byreverse-phase HPLC to yield 5.2 mg of the HCl salt of(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(1, 31%). LC-MS m/z 546.5 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.08 (d,J=1.6 Hz, 1H), 8.28 (s, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.0 Hz,2H), 7.64 (d, J=8.4 Hz, 2H), 5.03 (d, J=16.0 Hz, 1H), 4.91 (m, 2H), 4.82(m, 2H), 4.71 (s, 2H), 3.20 (q, J=7.2 Hz, 2H), 2.42-2.29 (m, 1H), 1.21(t, J=7.6 Hz, 3H), 1.17 (d, J=8.0 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).

Trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (was preparedfollowing the synthetic route shown in Scheme 10.

To a solution of trans-4-(trifluoromethyl)cyclohexane carboxylic acid(789 mg, 4.02 mmol) in THF (12 mL) at rt was added lithium aluminumhydride (1.0 M in THF, 4.02 mL). The mixture was heated to reflux andstirred for 3 h. It was then cooled to 0° C. and quenched successivelywith water (152 μL), 15% aqueous sodium hydroxide (152 μL), and water(456 μL). The mixture was then filtered through Celite and concentratedunder reduced pressure. The crude liquid(trans-4-(trifluoromethyl)cyclohexyl)methanol was carried forwardwithout any purification and without placing under high vacuum due toits volatility.

To a solution of oxalyl chloride (6.2 mL, 87.4 mmol) in anhydrous CH₂Cl₂(300 mL) was added dropwise DMSO (12.5 mL, 0.17 mol) at −78° C. underN₂. After the mixture was stirred at −78° C. for 30 min., a solution of(trans-4-(trifluoromethyl)cyclohexyl)methanol (5.3 g, 29.1 mmol) inCH₂Cl₂ (40 mL) was added dropwise while keeping the internal temperaturebelow −65° C. After being stirred for 30 min, a solution of Et₃N (40.5mL, 0.29 mol) in CH₂Cl₂ (60 mL) was added dropwise slowly, keeping theinternal temperature below −65° C. The reaction mixture was stirred at−78° C. for 1 h, and warmed to rt overnight. The mixture was washed withwater (3×300 mL) and brine (300 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica (eluting with 15% EtOAc inpetroleum ether) to givetrans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (4.6 g, 87%) as ayellow oil.

General Procedure B:(S)—N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(2)

To a solution of(S)—N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(3.6 g, 9.25 mmol), trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde(3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL) was added acetic aciddropwise until the pH was between 6 and 7. Sodium cyanoborohydride (1.7g, 27.75 mmol) was added portionwise at rt. The mixture was heated to70° C. for 1 h. Upon completion, the reaction mixture was cooled to rtand concentrated under reduced pressure. The residue was dissolved inethyl acetate (100 mL), then the organic phase was washed with water(3×100 mL) and brine (100 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 50%EtOAc in hexanes, gradient to 100%), then further purified by a chiralcolumn using the following conditions: instrument: Berger MultiGram™SFC, Mettler Toledo Co, Ltd; column: AD 300 mm×50 mm, 10 μm; mobilephase: A: supercritical CO₂, B: iPrOH (0.05% diethylamine), A:B=60:40 at200 mL/min; column temp: 38° C.; nozzle pressure: 100 bar; nozzle temp:60° C.; evaporator temp: 20° C.; trimmer temp: 25° C.; wavelength: 220nm. Isomer SFC t_(R)=2.28 min in 12 min chromatography was isolated asthe major isomer, which was then further purified by reverse-phase HPLCto give(S)—N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(2, HCl salt) as a light yellow solid. LC-MS t_(R)=0.69 min in 1 minchromatography, MS (ESI) m/z 553.1 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ9.12 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.75 (d, J=8.0Hz, 1H), 5.16 (d, J=15.6 Hz, 1H), 4.89-4.87 (m, 2H), 4.73 (d, J=15.2 Hz,1H), 3.42-3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58-2.51 (m, 1H), 2.20-1.90(m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz,3H), 1.24-1.20 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). HCl preparative HPLCmethod mobile phase A: water with 0.05% HCl; mobile phase B: CH₃CN; flowrate: 80 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex GeminiC18 (250 mm×50 mm×5 μm); column temperature: 30° C.

Time in min % A % B 0.00 75 25 25.00 50 50 30.00 0 100

A sample of 2 was converted to the HBr salt by the following procedure:The HCl salt of 2 (57.5 mg, 97.7 μmol) was dissolved in EtOAc (25 mL)and washed with saturated aqueous sodium bicarbonate (20 mL) and brine(10 mL). The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. It was then redissolved inacetonitrile (200 μL), to which was added hydrobromic acid (48 wt % inwater, 69 μL) to give a light yellow clear solution. The solvent wasremoved under reduced pressure, then more acetonitrile (300 μL) wasadded. This procedure was performed iteratively until most of the waterand excess HBr was removed, leaving behind a yellow solid. This solidwas redissolved in acetonitrile (6 mL), seeded with an HBr salt crystal(<1 mg), and stirred at rt for 30 min to give a white solid. The solidwas filtered and dried under high vacuum for 3 h to give the HBr salt(40.2 mg, 86%). Melting point=171-173° C. ¹H NMR (CD₃OD, 400 MHz): δ9.12 (s, 1H), 9.07 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 7.85(d, J=8.4 Hz, 1H), 5.18 (d, J=14.2 Hz, 1H), 4.94 (m, 1H), 4.87 (s, 2H),4.75 (d, J=14.2 Hz. 1H), 3.41 (m, 2H), 3.38 (q, J=7.6 Hz, 2H), 2.54 (m,1H), 2.17 (m, 1H), 2.04 (m, 5H), 1.45 (m, 2H), 1.32 (d, J=7.2 Hz, 3H),1.27 (t, J=7.6 Hz, 3H), 1.23 (m, 2H), 1.10 (d, J=6.4 Hz, 3H).

HBr seed crystals were formed as follows: 2 (5.6 mg) was converted tothe free base, then to the HBr salt, as described above. The resultantyellow solid was dissolved in acetonitrile (200 μL), then left to standovernight at rt in a capped vial. Colorless crystals formed, which wereidentified as plate-shaped under a microscope.

General Procedure C:(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(6)

To a solution of(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(27.3 mg, 70.4 μmol) in isopropanol (1.5 mL) in a MW vial was added2-chloro-5-(trifluoromethyl)pyrimidine (19.3 mg, 106 μmol) anddiisopropylethylamine (24.5 μL, 140.7 μmol). The vial was sealed andheated in the MW at 140° C. for 2 h. The solvent was then evaporated andthe residue was purified by silica gel chromatography (eluting with 60%EtOAc in hexanes, gradient to 100%), then further purified byreverse-phase HPLC to yield 7.2 mg of(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(6, 19%). LC-MS t_(R)=0.97 min in 1 min chromatography, MS (ESI) m/z534.5 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.34 (t, J=1.2 Hz, 1H), 8.97(s, 1H), 8.69 (d, J=4.8 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J=8.4 Hz, 2H),7.65 (d, J=8.0 Hz, 2H), 7.02 (d, J=4.8 Hz, 1H), 5.39 (s, 1H), 5.14 (d,J=15.6 Hz, 1H), 4.87 (m, 1H), 4.72 (d, J=6.0 Hz, 2H), 3.20 (q, J=7.6 Hz,2H), 2.79-2.68 (m, 1H), 1.22 (broad s, 3H), 1.21 (t, J=7.6 Hz, 3H), 0.69(broad s, 3H).

General Procedure D:(S)-6-((4-cyanophenyl)sulfonyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(13)

To a solution of(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(6.9 mg, 17.8 μmol) in CH₂Cl₂ (600 μL) was added triethylamine (5.0 μL,36.6 μmol) and 4-cyanobenzenesulfonyl chloride (5.4 mg, 26.8 μmol). Themixture was stirred at rt for 15 h, at which point it was quenched withsaturated aqueous sodium bicarbonate (10 mL). The mixture was extractedwith EtOAc (10 mL), then the organic phase was washed with brine (10mL), dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by reverse-phase HPLC to yield 4.9 mgof(S)-6-((4-cyanophenyl)sulfonyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamideas an HCl salt (13, 46%). LC-MS t_(R)=0.84 min in 1 min chromatography,MS (ESI) m/z 553.5 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 8.85 (d, J=2.0 Hz,1H), 8.09 (d, J=1.6 Hz, 1H), 8.03 (dd, J=2.0 Hz, 8.8 Hz, 2H), 7.86 (m,4H), 7.60 (d, J=8.4 Hz, 2H), 4.93 (m, 2H), 4.73 (dt, J=1.2 Hz, 16.4 Hz,1H), 4.66 (s, 2H), 3.19 (q, J=7.6 Hz, 2H), 2.41-2.32 (m, 1H), 1.20 (t,J=7.6 Hz, 3H), 1.00 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).

General Procedure E: benzyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(16)

To a solution of(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(11.3 mg, 29.2 μmol) in CH₂Cl₂ (1 mL) was added benzyl chloroformate(11.7 μL, 3.0 M in toluene), triethylamine (6.1 μL, 43.8 μmol) and4-dimethylaminopyridine (50 μg, 4.09 μmol). The mixture was stirred atrt for 15 h, at which point it was quenched with saturated aqueoussodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10mL), then the organic phase was washed with brine (10 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 30%EtOAc in hexanes, gradient to 100%), then further purified byreverse-phase HPLC to yield 14.9 mg of benzyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas an HCl salt (16, 91%). LC-MS t_(R)=0.91 min in 1 min chromatography,MS (ESI) m/z 522.5 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.00 (s, 1H), 8.34(s, 1H), 7.87 (dd, J=1.6 Hz, 6.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.42(dd, J=1.6 Hz, 8.4 Hz, 2H), 7.33 (m, 3H), 5.20 (m, 3H), 4.96 (m, 1H),4.71 (m, 3H), 3.20 (q, J=7.6 Hz, 2H), 2.57-2.36 (m, 1H), 1.19 (t, J=7.6Hz, 3H), 1.00 (dd, J=6.8 Hz, 16.0 Hz, 3H), 0.78 (dd, J=6.8 Hz, 25.6 Hz,3H).

(7S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidewas prepared following the synthetic route shown in Scheme 11.

To a solution of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate(104 mg, 291 μmol) and N,O-dimethylhydroxylamine hydrochloride (45.5 mg,466 μmol) in THF (1 mL) was added dropwise methylmagnesium bromide (1.4M in 3:1 toluene:THF, 1.04 mL) at −20° C. The mixture was stirred at−20° C. for 45 min, at which point it was quenched carefully with coldsaturated aqueous ammonium chloride (10 mL). The mixture was extractedwith EtOAc (20 mL), then the organic phase was washed with brine (10mL), dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith 10% EtOAc in hexanes, gradient to 60%) to afford 62.3 mg oftert-butyl(S)-(1-(3-acetyl-5-chloropyridin-2-yl)-2-methylpropyl)carbamate (56%yield). LC-MS t_(R)=1.08 min in 1 min chromatography, MS (ESI) m/z 327.4[M+H]⁺.

To a solution of tert-butyl(S)-(1-(3-acetyl-5-chloropyridin-2-yl)-2-methylpropyl)carbamate (62.3mg, 191 μmol) in EtOH (1 mL) at 0° C. was added sodium borohydride (7.2mg, 191 μmol) as a solid. The mixture was stirred at 0° C. for 90 min,then it was quenched with saturated aqueous ammonium chloride (10 mL).The mixture was extracted with EtOAc (20 mL), then the organic phase waswashed with brine (10 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%)to afford 53.4 mg of tert-butyl((1S)-1-(5-chloro-3-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropyl)carbamate(85% yield). LC-MS t_(R)=1.01 min in 1 min chromatography, MS (ESI) m/z329.4 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz, mixture of diastereomers): δ 8.44(d, J=2.4 Hz, 0.3H), 8.41 (d, J=2.4 Hz, 0.7H), 7.86 (d, J=2.4 Hz, 0.7H),7.77 (d, J=2.4 Hz, 0.3H), 5.44 (d, J=9.6 Hz, 0.7H), 5.31 (m, 0.7H), 5.23(m, 0.7H), 4.73 (t, J=8.8 Hz, 0.3H), 4.63 (t, J=9.6 Hz, 0.3H), 4.56 (s,0.3H), 2.18-2.12 (m, 0.3H), 2.08-2.00 (m, 0.7H), 1.56 (d, J=6.8 Hz,0.9H), 1.52 (d, J=6.8 Hz, 2.1H), 1.40 (s, 9H), 1.11 (d, J=6.8 Hz, 0.9H),1.00 (d, J=6.8 Hz, 2.1H), 0.80 (d, J=6.8 Hz, 2.1H), 0.69 (d, J=6.8 Hz,0.9H).

1-(2-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)ethylmethanesulfonate. Procedure same as that for(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methylmethanesulfonate, using tert-butyl((1S)-1-(5-chloro-3-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropyl)carbamateas a starting material. LC-MS t_(R)=1.03 min in 1 min chromatography, MS(ESI) m/z 407.4 [M+H]⁺.

Tert-butyl(7S)-3-chloro-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate.Procedure same as that for tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,using1-(2-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)ethylmethanesulfonate as a starting material. LC-MS t_(R)=1.12 min in 1 minchromatography, MS (ESI) m/z 311.4 [M+H]⁺. ¹H NMR (CDCl₃, 400 MHz,mixture of diastereomers): δ 8.43 (d, J=1.6 Hz, 1H), 7.52 (s, 0.7H),7.46 (s, 0.3H), 5.05-5.00 (m, 1H), 4.94 (s, 0.3H), 4.81 (s, 0.7H),2.88-2.39 (m, 0.3H), 2.32-2.08 (m, 0.7H), 1.55 (m, 3H), 1.44 (s, 9H),1.26 (d, J=7.2 Hz, 0.9H), 1.09 (broad s, 2.1H), 0.81 (broad s, 2.1H),0.48 (d, J=7.2 Hz, 0.9H).

(7S)-6-(tert-butoxycarbonyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid. Procedure same as that for(S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid, using tert-butyl(7S)-3-chloro-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material. LC-MS t_(R)=0.99 min in 1 min chromatography, MS(ESI) m/z 321.5 [M+H]⁺.

Tert-butyl(7S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate.Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,using(7S)-6-(tert-butoxycarbonyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid as a starting material. LC-MS t_(R)=0.95 min in 1 minchromatography, MS (ESI) m/z 502.6 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz,mixture of diastereomers): δ 8.93 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.50(d, J=8.4 Hz, 2H), 7.24 (s, 1H), 5.06-4.88 (m, 2H), 4.82-4.70 (m, 2H),3.06 (q, J=7.2 Hz, 2H), 2.48-2.26 (m, 1H), 1.59 (d, J=7.2 Hz, 0.9H),1.56 (d, J=7.2 Hz, 2.1H), 1.53 (s, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.09 (d,J=7.2 Hz, 0.9H), 0.97 (broad s, 2.1H), 0.83 (broad s, 2.1H), 0.48 (d,J=7.2 Hz, 0.9H).

(7S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide.Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using tert-butyl(7S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material. LC-MS t_(R)=0.49 min in 1 min chromatography, MS(ESI) m/z 402.3 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz, mixture ofdiastereomers): δ 8.91 (dd, J=1.2 Hz, 2.0 Hz, 1H), 8.11 (dd, J=0.8 Hz,2.0 Hz, 0.4H), 8.07 (dd, J=1.2 Hz, 1.6 Hz, 0.6H), 7.89 (d, J=8.4 Hz,2H), 7.63 (d, J=8.4 Hz, 2H), 4.70 (s, 2H), 4.57 (m, 0.4H), 4.48 (m,0.6H), 4.30 (m, 1H), 3.20 (q, J=7.2 Hz, 2H), 2.40-2.33 (m, 0.6H),2.27-2.21 (m, 0.4H), 1.50 (d, J=6.8 Hz, 1.8H), 1.47 (d, J=7.2 Hz, 1.2H),1.20 (t, J=7.6 Hz, 3H), 1.14 (d, J=7.2 Hz, 1.8H), 1.08 (d, J=7.2 Hz,1.2H), 0.81 (d, J=6.8 Hz, 1.2H), 0.80 (d, J=6.8 Hz, 1.8H).

N-(4-(ethylsulfonyl)benzyl)-7-(tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamidewas prepared following the synthetic route shown in Scheme 12.

To a solution of 2-amino-2-(tetrahydrofuran-3-yl)acetic acidhydrochloride (1 g, 5.52 mmol) in a mixture of THF (15 mL) and water(1.5 mL) was added di-tert-butyl dicarbonate (1.2 g, 5.52 mmol) andsodium hydroxide (0.9 g, 22.1 mmol). The mixture was stirred at rtovernight. Water (50 mL) was added to the mixture, followed byacidification with 2N aq. HCl solution to pH=2. The mixture wasextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, concentrated under reducepressure to afford2-((tert-butoxycarbonyl)amino)-2-(tetrahydrofuran-3-yl)acetic acid (1.11g, 80%) as a colorless oil, which was used for the next step withoutfurther purification. MS: MS (ESI) m/z 268.1180 [M+Na]⁺.

Ethyl4-((tert-butoxycarbonyl)amino)-3-oxo-4-(tetrahydrofuran-3-yl)butanoate.Procedure same as that for ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate, using2-((tert-butoxycarbonyl)amino)-2-(tetrahydrofuran-3-yl)acetic acid as astarting material. ¹H NMR (CD₃OD, 400 MHz): δ 4.25-4.13 (m, 3H),4.00-3.45 (m, 4H), 2.75-2.65 (m, 1H), 2.12-1.98 (m, 1H), 1.77-1.62 (m,1H), 1.49 (s 9H), 1.30 (t, J=7.2 Hz, 3H).

Ethyl2-(((tert-butoxycarbonyl)amino)(tetrahydrofuran-3-yl)methyl)-5-chloronicotinate.Procedure same as that for ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate,using ethyl4-((tert-butoxycarbonyl)amino)-3-oxo-4-(tetrahydrofuran-3-yl)butanoateas a starting material. ¹H NMR (CD₃OD, 400 MHz): δ 8.73 (s, 1H), 8.24(s, 1H), 5.66 (d, J=8.0 Hz, 1H), 4.61 (s, 1H), 4.45 (q, J=6.8 Hz, 2H),3.92-3.86 (m, 1H), 3.82-3.56 (m, 3H), 2.82-2.86 (m, 1H), 1.95 (q, J=7.2Hz, 1H), 1.74 (q, J=6.8 Hz, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.8Hz, 9H).

Tert-butyl((5-chloro-3-(hydroxymethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate.Procedure same as that for tert-butyl(S)-(1-(5-chloro-3-(hydroxymethyl)pyridin-2-yl)-2-methylpropyl)carbamate,using ethyl2-(((tert-butoxycarbonyl)amino)(tetrahydrofuran-3-yl)methyl)-5-chloronicotinateas a starting material. LCMS: t_(R)=0.753 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 342.9 [M+H]⁺.

To a solution of tert-butyl((5-chloro-3-(hydroxymethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate(600 mg, 1.74 mmol) in anhydrous CH₂Cl₂ (25 mL) was added Et₃N (0.5 mL,2.62 mmol) and p-toluenesulfonyl chloride (400 mg, 2.1 mmol) at 0° C.The mixture was stirred at rt for 2 h. The mixture was then washed withwater (3×20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure and purified bychromatography column on silica gel (eluting with 10% EtOAc in petroleumether, gradient to 20%) to afford(2-(((tert-butoxycarbonyl)amino)(tetrahydrofuran-3-yl)methyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate (470 mg, 54%) as a colorless oil and tert-butyl((5-chloro-3-(chloromethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate(200 mg, 32%) as a white solid. LCMS: t_(R)=0.947 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 519.1 [M+Na]⁺.

To a solution of tert-butyl((5-chloro-3-(chloromethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate(470 mg, 0.95 mmol) in anhydrous DMF (5 mL) was added with sodiumhydride (115 mg, 2.84 mmol, 60% in mineral oil) in portions at 0° C. Themixture was stirred at rt for 2 h. The mixture was quenched with water(40 mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure and purified by chromatography column on silicagel (eluting with 10% EtOAc in petroleum ether) to afford tert-butyl3-chloro-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(285 mg, 91%) as a colorless oil. LCMS: t_(R)=0.862 min in 5-95AB_1.5min chromatography (MK RP-18e 25-2 mm), MS (ESI) m/z 324.9 [M+H]⁺. ¹HNMR (CD₃OD, 400 MHz): δ 8.47 (s, 1H), 7.83 (d, J=13.6 Hz, 1H), 5.10 (s,1H), 4.65-4.50 (m, 1.5H), 3.95 (t, J=8.0 Hz, 0.5H), 3.85-3.67 (m, 4H),3.03-2.87 (m, 1H), 2.15-1.65 (m, 2H), 1.54 (s, 9H).

To a solution of tert-butyl3-chloro-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(60 mg, 0.19 mmol) in a MW vial in anhydrous dioxane (0.5 mL) was addedmolybdenum hexacarbonyl (6 mg, 0.02 mmol),(4-(ethylsulfonyl)phenyl)methanamine (56 mg, 0.28 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (90 mg, 0.57 mmol). The mixture wasdegassed with N₂ for 15 min, at which point tri-tert-butylphosphoniumtetrafluoroborate (58 mg, 0.19 mmol) andtrans-bis(acetate)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (10mg, 0.01 mmol) were added. The vial was sealed and heated in the MW at160° C. for 20 min. The reaction mixture was filtered, then the filtratewas concentrated under reduced pressure and purified by preparative TLC(eluting with 12% EtOAc in petroleum ether) to afford tert-butyl3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(25 mg, 26%) as a colorless oil. LCMS: t_(R)=0.761 min in 5-95AB_1.5 minchromatography (MK RP18e 25-2 mm), MS (ESI) m/z 516.2 [M+H]⁺. ¹H NMR(CD₃OD, 400 MHz): δ 8.96 (s, 1H), 8.20 (d, J=10.0 Hz, 1H), 8.15-8.00 (m,1H), 7.91 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 5.19 (s, 1H),5.00-4.90 (m, 2H), 4.75-4.60 (m, 3H), 4.00-3.65 (m, 5H), 3.25 (q, J=7.2Hz, 2H), 3.05-2.95 (m, 1H), 2.15-1.75 (m, 2H), 1.56 (s, 9H), 1.23 (t,J=7.2 Hz, 3H).

N-(4-(ethylsulfonyl)benzyl)-7-(tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide.Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using tert-butyl3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material.

(S)-6-(4-chlorobenzyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(9) was prepared following the synthetic route shown in Scheme 13.

Ethyl (S)-2-(1-amino-2-methylpropyl)-5-chloronicotinate. Procedure sameas that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinateas a starting material. LCMS: t_(R)=0.59 min in in 1 min chromatography,MS (ESI) m/z 257.3 [M+H]⁺.

A solution of ethyl (S)-2-(1-amino-2-methylpropyl)-5-chloronicotinate(282 mg, 1.10 mmol) was heated in toluene (5 mL) at 100° C. for 15 h.The solvent was removed in vacuo to yield crude(S)-3-chloro-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one,which was carried forward without further purification. LCMS: t_(R)=0.73min in in 1 min chromatography, MS (ESI) m/z 211.2 [M+H]⁺. ¹H NMR(CD₃OD, 400 MHz): δ 8.70 (d, J=2.8 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 6.75(broad s, 1H), 4.55 (dd, J=1.2 Hz, 3.6 Hz, 1H), 2.49-2.41 (m, 1H), 1.23(d, J=7.2 Hz, 3H), 0.74 (d, J=6.8 Hz, 3H).

To a degassed solution of(S)-3-chloro-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(42.2 mg, 200 μmol) in THF (2 mL) at 0° C. was added sodium hydride (60%dispersion in mineral oil, 9.6 mg, 240 μmol). The mixture was stirred at0° C. for 30 min, at which point 4-chlorobenzyl bromide (49.3 mg, 240μmol) was added. The mixture was allowed to warm to rt and was stirredfor 15 h. The mixture was quenched with saturated aqueous ammoniumchloride (10 mL) and extracted with EtOAc (10 mL). The organic phase waswashed with brine (10 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluting with 5% EtOAc in hexanes, gradient to 50%)to afford(S)-3-chloro-6-(4-chlorobenzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(19.6 mg, 29%) and3-chloro-6-(4-chlorobenzyl)-7-hydroxy-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(20.1 mg, 29%). LCMS: t_(R)=1.09 min in in 1 min chromatography, MS(ESI) m/z 335.3 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 8.74 (d, J=2.0 Hz,1H), 8.17 (d, J=2.4 Hz, 1H), 7.37-7.32 (m, 4H), 5.16 (d, J=15.6 Hz, 1H),4.47 (d, J=15.2 Hz, 1H), 4.40 (d, J=3.2 Hz, 1H), 2.56-2.48 (m, 1H), 1.27(d, J=7.2 Hz, 3H), 0.48 (d, J=7.2 Hz, 3H).

General Procedure F:(S)-6-(4-chlorobenzyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide(9)

Procedure same as that for tert-butyl3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(Scheme 12), using(S)-3-chloro-6-(4-chlorobenzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneas a starting material. LCMS: t_(R)=0.92 min in in 1 min chromatography,MS (ESI) m/z 526.4 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.22 (d, J=2.0 Hz,1H), 8.57 (d, J=2.0 Hz, 1H), 7.90 (dd, J=2.0 Hz, 6.8 Hz, 2H), 7.66 (d,J=8.8 Hz, 2H), 7.36 (m, 4H), 5.19 (d, J=15.6 Hz, 1H), 4.73 (s, 2H), 4.48(m, 2H), 3.20 (q, J=7.2 Hz, 2H), 2.60-2.52 (m, 1H), 1.29 (d, J=7.2 Hz,3H), 1.21 (t, J=7.2 Hz, 3H), 0.49 (d, J=6.8 Hz, 3H).

(S)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid was prepared following the synthetic route shown in Scheme 14.

To a solution of 6-(tert-butyl) 3-methyl(S)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-3,6-dicarboxylate(296 mg, 0.92 mmol) in MeOH (3 mL) was added HCl (4 mL, 4.0 M indioxane). The mixture was stirred for 30 min at rt for 30 min. Thereaction mixture was concentrated to dryness to give methyl(S)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate asthe HCl salt. LC-MS t_(R)=0.56 min in 2 min chromatography, MS (ESI) m/z221 [M+H]⁺.

6-(tert-butyl) 3-methyl(S)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-3,6-dicarboxylate.Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using methyl(S)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate as astarting material. LC-MS t_(R)=1.45 min in 2 min chromatography, MS(ESI) m/z 379 [M+H]⁺.

To a solution of 6-(tert-butyl) 3-methyl(S)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-3,6-dicarboxylate(216 mg, 674 μmol) in MeOH (4 mL) was added 10% aqueous Na₂S₂O₃ (3drops) and aqueous lithium hydroxide (1.2 mL, 2.0 M). The mixture wasstirred for 3 h at rt. The reaction mixture was then concentrated, andthe residue was purified by preparative HPLC to give 230 mg of(S)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid as the TFA salt. LC-MS t_(R)=1.22 min in 2 min chromatography, MS(ESI) m/z 365 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz): δ 9.14, (s, 1H), 8.35 (s1H), 7.84-7.81 (m, 4H), 4.81-4.58 (m, 5H), 2.38 (m, 1H), 1.13 (d, J=6.8Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).

General Procedure G: tert-butyl(S)-7-isopropyl-3-((4-(methoxycarbonyl)benzyl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

Tert-butyl(S)-7-isopropyl-3-((4-(methoxycarbonyl)benzyl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate.Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,using methyl 4-(aminomethyl)benzoate as a starting material. LC-MSt_(R)=1.61 min in 2 min chromatography, MS (ESI) m/z 454.

(S)-4-((7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoicacid was prepared following the synthetic route shown in Scheme 15.

Methyl(S)-4-((7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoate.Procedure same as that for methyl(S)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate,using tert-butyl(S)-7-isopropyl-3-((4-(methoxycarbonyl(benzyl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateas a starting material. LC-MS t_(R)=0.73 min in 2 min chromatography, MS(ESI) m/z 354.

Methyl(S)-4-((7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoate(65). Procedure same as that for(S)—N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,using methyl(S)-4-((7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoateas a starting material. LC-MS t_(R)=1.34 min in 2 min chromatography, MS(ESI) m/z 512 [M+H]⁺.

General Procedure H

(S)-4-((7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoicacid (147). Procedure same as that for(S)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylicacid, using methyl(S)-4-((7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoateas a starting material. LC-MS t_(R)=1.20 min in 2 min chromatography, MS(ESI) m/z 498 [M+H]⁺.

The following compounds in Table 1 were prepared according to themethods described herein.

TABLE 1 Cmpd No. Structure LCMS ¹H-NMR 3

512.4 (M + H)+ (CD₃OD) δ 9.36 (t, J = 1.2 Hz, 1H), 9.05 (s, 1H), 8.23(s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.59 (d, J= 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.90 (m, 1H), 4.74 (m, 4H),4.57 (s, 2H), 3.20 (q, J = 7.6 Hz, 2H), 2.42-2.29 (m, 1H), 1.21 (t, J =7.6 Hz, 3H), 1.13 (d, 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 4

503.5 (M + H)+ (CD₃OD) δ 9.36 (t, J = 1.2 Hz, 1H), 9.03 (s, 1H), 8.21(s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 4.84 (d, J = 15.6 Hz, 1H), 4.71(m, 3H), 4.59 (m, 3H), 3.20 (q, J = 7.6 Hz, 2H), 2.43-2.32 (m, 1H), 1.21(t, J = 7.2 Hz, 3H), 1.12 (d, 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H). 5

544.4 (M + H)+ (CD₃OD) δ 9.36 (t, J = 1.2 Hz, 1H), 9.04 (s, 1H), 8.23(s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.4 Hz, 4H), 7.27 (d, J= 8.4 Hz, 2H), 6.92 (t, J = 73.6 Hz, 1H), 4.90 (m, 2H), 4.72 (m, 3H),4.56 (m, 2H), 3.20 (q, J = 7.6 Hz, 2H), 2.40-2.29 (m, 1H), 1.21 (t, J =7.6 Hz, 3H), 1.12 (d, 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 7

496.5 (M + H)+ (CD₃OD) δ 9.06 (s, 1H), 8.26 (s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.66 (m, 4H), 7.26 (d, J = 8.4 Hz, 2H), 4.96 (d, J = 15.6 Hz,1H), 4.82 (m, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.64 (d, J = 13.2 Hz, 1H),4.59 (d, J = 13.2 Hz, 1H), 3.20 (q, J = 7.6 Hz, 2H), 2.42-2.33 (m, 1H),1.21 (t, J = 7.2 Hz, 3H), 1.12 (d, 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz,3H). 8

534.4 (M + H)+ (CD₃OD) δ 8.97 (d, J = 2.0 Hz, 1H), 8.68 (s, 2H), 8.25(t, J = 0.8 Hz, 1H), 7.89 (dd, J = 1.6 Hz, 8.4 Hz, 2H), 7.65 (d, J = 8.4Hz, 2H), 5.39 (dd, J = 2.0 Hz, 3.2 Hz, 1H), 5.15 (d, J = 16.4 Hz, 1H),4.88 (d, J = 16.4 Hz, 1H), 4.72 (s, 2H), 3.20 (q, J = 7.2 Hz, 2H),2.80-2.71 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H),0.64 (d, J = 6.8 Hz, 3H). 10

606.6 (M + H)+ (CD₃OD) δ 9.02 (d, J = 7.6 Hz, 1H), 8.99 (s, 1H), 8.26(s, 1H), 7.90 (dd, J = 2.0 Hz, 6.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H),5.44 (d, J = 9.2 Hz, 1H), 5.22 (dd, J = 10.0 Hz, 16.8 Hz, 1H), 4.93 (d,J = 16.4 Hz, 1H), 4.72 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.20 (q, J =7.6 Hz, 2H), 2.81-2.70 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.21 (t, J =7.6 Hz, 3H), 0.88 (dd, J = 7.2 Hz, 13.2 Hz, 3H), 0.69 (dd, J = 7.2 Hz,17.6 Hz, 3H). 11

542.5 (M + H)+ (CD₃OD) δ 9.23 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz,1H), 7.90 (dd, J = 2.0 Hz, 6.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.49(d, J = 8.4 Hz, 2H), 7.32 (dd, J = 2.0 Hz, 6.8 Hz, 2H), 4.80 (d, J =14.0 Hz, 1H), 4.73 (m, 2H), 4.61 (d, J = 15.2 Hz, 1H), 3.20 (q, J = 7.2Hz, 2H), 2.48- 2.41 (m, 1H), 1.27 (d, 6.8 Hz, 3H), 1.20 (t, J = 7.2 Hz,3H), 0.39 (d, J = 7.2 Hz, 3H). 12

564.5 (M + H)+ (CD₃OD) δ 9.02 (2, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.90(dd, J = 1.6 Hz, 6.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 5.51 (t, J = 2.8Hz, 1H), 5.21 (d, J = 16.4 Hz, 1H), 4.93 (m, 1H), 4.73 (s, 2H), 4.67 (s,2H), 3.20 (q, J = 7.2 Hz, 2H), 2.78-2.66 (m, 1H), 1.21 (t, J = 7.2 Hz,3H), 1.17 (d, J = 5.6 Hz, 3H), 0.78 (d, J = 5.6 Hz, 3H). 14

578.5 (M + H)+ (CD₃OD) δ 9.09 (d, J = 2.0 Hz, 1H), 8.93 (s, 1H), 8.59(s, 1H), 7.90 (dd, J = 1.6 Hz, 6.8 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H),5.64 (dd, J = 3.2 Hz, 7.0 Hz, 1H), 5.28 (d, J = 16.4 Hz, 1H), 5.13 (q, J= 6.4 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 4.74 (s, 2H), 3.20 (q, J = 7.6Hz, 2H), 2.76- 2.66 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.2Hz, 3H), 1.13 (d, 6.8 Hz, 3H), 0.81 (dd, J = 6.8 Hz, 3H). 17

498.0 (M + H)+ (CD₃OD) δ 9.39 (brs, 1H), 9.09 (s, 1H), 8.28 (s, 1H),7.96 (d, J = 8.4 Hz, 2H), 7.70-7.60 (m, 4H), 7.56 (d, J = 8.0 Hz, 2H),5.05-4.95 (m, 2H), 4.75-4.60 (m, 5H), 3.13 (s, 3H), 2.39-2.35 (m, 1H),1.16 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 18

498.0 (M + H)+ (CD₃OD) δ 9.08 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 7.96(dd, J = 1.6, 6.8 Hz, 2H), 7.67-7.63 (m, 4H), 7.55 (d, J = 8.4 Hz, 2H),5.10-4.95 (m, 2H), 4.75-4.60 (m, 5H), 3.13 (s, 3H), 2.38-2.34 (m, 1H),1.14 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 7.2 Hz, 3H). 19

489.1 (M + H)+ (CD₃OD) δ 9.07 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 7.96(dd, J = 2.0, 6.8 Hz, 2H), 7.88 (dd, J = 8.8, 22.4 Hz, 4H), 7.65 (d, J =8.4 Hz, 2H), 4.85-4.65 (m, 7H), 3.13 (s, 3H), 2.42- 2.37 (m, 1H), 1.16(d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). 20

489.0 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.30 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.91 (s, 4H), 7.66 (d, J = 8.4 Hz, 2H), 5.07 (d, J = 15.6 Hz,1H), 4.90- 4.70 (m, 3H), 4.72 (s, 3H), 3.13 (s, 3H), 2.42-2.37 (m, 1H),1.16 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 21

489.0 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.30 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.91 (s, 4H), 7.66 (d, J = 8.4 Hz, 2H), 5.07 (d, J = 15.6 Hz,1H), 4.90- 4.70 (m, 3H), 4.72 (s, 3H), 3.13 (s, 3H), 2.42-2.37 (m, 1H),1.16 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 22

532.1 (M + H)+ (CD₃OD) δ 9.09 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.95(d, J = 8.0 Hz, 2H), 8.88 (q, J = 8.4 Hz, 4H), 7.66 (d, J = 8.4 Hz, 2H),5.04 (d, J = 15.2 Hz, 2H), 4.85- 4.70 (m, 5H), 3.13 (s, 3H), 2.41-2.37(m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 23

499.1 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.32(s, 1H), 8.00 (dd, J = 2.4, 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.66(d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 1H), 5.15 (d, J = 16.0 Hz,2H), 4.85-4.75 (m, 3H), 4.73 (s, 2H), 3.13 (s, 3H), 2.62-2.54 (m, 1H),1.22 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). 24

482.1 (M + H)+ (CD₃OD) δ 9.08 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 7.95(d, J = 8.4 Hz, 2H), 7.75 (dd, J = 4.8, 8.4 Hz, 2H), 7.66 (d, J = 8.4Hz, 2H), 7.28 (t, J = 8.4 Hz, 2H), 5.10-5.03 (m, 2H), 4.90-4.70 (m, 4H),4.59 (d, J = 12.8 Hz, 1H), 3.13 (s, 3H), 2.37-2.30 (m, 1H), 1.11 (d, J =6.4 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 25

556.6 (M + H)+ (CD₃OD) δ 8.96 (s, 1H), 8.22 (d, J = 11.6 Hz, 1H), 7.89(d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H),7.38 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 5.07 (m, 1H), 4.85 (m, 2H), 4.71(s, 2H), 3.20 (q, J = 7.2 Hz, 2H), 2.58-2.39 (m, 1H), 1.21 (t, J = 7.2Hz, 3H), 1.03 (dd, 6.8 Hz, 16.8 Hz, 3H), 0.75 (dd, J = 6.8 Hz, 18.8 Hz,3H). 26

548.5 (M + H)+ (CD₃OD) δ 9.30 (s, 2H), 9.09 (s, 1H), 8.30 (s, 2H), 7.89(dd, J = 2.0 Hz, 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.95 (m, 3H),4.82 (m, 2H), 4.71 (s, 2H), 3.20 (q, J = 7.2 Hz, 2H), 2.62-2.53 (m, 1H),1.25 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 0.98 (d, J = 6.8 Hz,3H). 27

547.5 (M + H)+ (CD₃OD) δ 9.08 (d, J = 1.6 Hz, 1H), 9.03 (s, 1H), 8.32(d, J = 1.6 Hz, 1H), 8.26 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 5.18 (d, J= 15.6 Hz, 1H), 4.97 (s, 2H), 4.92 (m, 2H), 4.72 (s, 2H), 3.20 (q, J =7.6 Hz, 2H), 2.68-2.59 (m, 1H), 1.24 (d, J = 7.2 Hz, 3H), 1.21 (t, J =7.6 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). 28

526.3 (M + H)+ (CD₃OD) δ 9.11 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 8.8Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.59 (m, 4H), 5.25-4.83 (m, 2H), 4.73(s, 2H), 4.62 (m, 1H), 4.15 (m, 1H), 3.20 (q, J = 7.2 Hz, 2H), 2.21-2.10(m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 0.95 (m,3H), 0.79 (d, J = 6.8 Hz, 3H). 29

526.3 (M + H)+ (CD₃OD) δ 9.07 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 7.89(dd, J = 2.0 Hz, 6.8 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H), 7.64 (d, J = 8.0Hz, 2H), 7.57 (m, 2H), 5.21 (q, J = 6.8 Hz, 1H), 4.99 (d, J = 3.2 Hz,1H), 4.82 (d, J = 3.6 Hz, 1H), 4.72 (m, 3H), 3.20 (q, J = 7.2 Hz, 2H),2.16- 2.09 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H),1.21 (t, J = 7.2 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 30

560.6 (M + H)+ (CD₃OD) δ 9.11 (s, 1H), 8.32 (s, 1H), 7.87 (m, 6H), 7.66(d, J = 8.0 Hz, 2H), 5.35 (m, 1H), 4.83 (m, 1H), 4.73 (s, 2H), 4.63 (m,1H), 4.28 (m, 1H), 3.21 (q, J = 7.2 Hz, 2H), 2.23-2.11 (m, 1H), 1.97 (d,J = 6.8 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 0.97 (m, 3H), 0.80 (d, J =6.8 Hz, 3H). 31

560.6 (M + H)+ (CD₃OD) δ 9.08 (d, J = 1.2 Hz, 1H), 8.24 (s, 1H), 7.95(d, J = 8.4 Hz, 2H), 7.89 (m, 4H), 7.64 (d, J = 8.8 Hz, 2H), 5.24 (m,1H), 5.01 (d, J = 2.8 Hz, 1H), 4.88 (m, 2H), 4.71 (s, 2H), 3.20 (q, J =7.6 Hz, 2H), 2.18- 2.10 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H), 1.28 (d, J =6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 32

560.5 (M + H)+ (CD₃OD) δ 9.23 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.4 Hz,1H), 7.90 (d, J = 8.8 Hz, 2H), 7.65 (m, 4H), 7.55 (d, J = 8.8 Hz, 2H),5.26 (d, J = 15.6 Hz, 1H), 4.74 (s, 2H), 4.63 (d, J = 16.4 Hz, 1H), 4.53(d, J = 3.2 Hz, 1H), 3.20 (q, J = 7.2 Hz, 2H), 2.60-2.52 (m, 1H), 1.30(d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 0.50 (d, J = 6.8 Hz, 3H).33

547.5 (M + H)+ (CD₃OD) δ 9.12 (s, 1H), 9.10 (d, J = 1.2 Hz, 1H), 8.53(dd, J = 2.0 Hz, 8.4 Hz, 1H), 8.34 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H),7.91 (d, J = 6.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 5.07 (d, J = 15.6Hz, 1H), 4.84 (m, 3H), 4.73 (d, J = 12.8 Hz, 1H), 3.35 (q, J = 7.2 Hz,2H), 2.42-2.29 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 6.8 Hz,3H), 0.89 (d, J = 6.8 Hz, 3H). 34

513.5 (M + H)+ (CD₃OD) δ 9.13 (dd, J = 1.6 Hz, 3.6 Hz, 2H), 8.59 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 8.35 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.70 (d,J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 5.07 (d, J = 15.2 Hz, 1H),4.87 (m, 2H), 4.73 (d, J = 13.2 Hz, 1H), 4.60 (d, J = 12.8 Hz, 1H), 3.37(q, J = 7.6 Hz, 2H), 2.41- 2.25 (m, 1H), 1.29 (t, J = 7.6 Hz, 3H), 1.12(d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). 35

504.5 (M + H)+ (CD₃OD) δ 9.11 (d, J = 2.0 Hz, 2H), 8.56, (dd, J = 2.0Hz, 8.4 Hz, 1H), 8.33 (s, 1H), 8.01- 7.79 (m, 5H), 5.07 (d, J = 15.2 Hz,1H), 4.91-4.80 (m, 3H), 4.72 (d, J = 14.4 Hz, 1H), 3.36 (q, J = 7.2 Hz,2H), 2.64-2.53 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 6.8 Hz,3H), 0.89 (d, J = 7.2 Hz, 3H). 36

533.1 (M + H)+ (CD₃OD) δ 9.09 (s, 1H), 9.04 (s, 1H), 8.33 (s, 1H), 8.28(d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H),7.66 (d, J = 8.4 Hz, 2H), 5.20 (d, J = 15.6 Hz, 1H), 5.25-4.93 (m, 4H),4.73 (s, 2H), 3.13 (s, 3H), 2.68- 2.63 (m, 1H), 1.25 (d, J = 6.8 Hz,3H), 0.98 (d, J = 6.8 Hz, 3H). 37

533.0 (M + H)+ (CD₃OD) δ 9.43 (t, J = 6.0 Hz, 1H), 9.07 (d, J = 18.8 Hz,2H), 8.33-8.25 (m, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.0, 1H),7.66 (d, J = 8.4 Hz, 2H), 5.20-4.92 (m, 5H), 4.73 (d, J = 6.0, 2H), 3.13(s, 3H), 2.68-2.61 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 6.8Hz, 3H). 38

560.1 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.31 (s, 1H), 8.26 (d, J = 8.0Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 2H), 5.10 (d, J = 15.2 Hz, 1H), 4.99-4.96 (m, 1H), 4.85-4.77(m, 2H), 4.73-4.67 (m, 3H), 4.46 (s, 3H), 3.22 (q, J = 7.6 Hz, 2H),2.38- 2.32 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H),0.90 (d, J = 6.8 Hz, 3H). 39

547.1 (M + H)+ (CD₃OD) δ 9.10 (d, J = 2.0 Hz, 1H), 9.05 (s, 1H), 8.46(dd, J = 2.0, 8.0 Hz, 1H), 8.31 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.91(d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 5.06- 4.98 (m, 2H), 4.86-4.81 (m, 3H), 4.73 (s, 2H), 3.22 (q, J = 7.6 Hz, 2H), 2.52- 2.48 (m,1H), 1.23- 1.19 (m, 6H), 0.94 (d, J = 6.8 Hz, 3H). 40

547.1 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.99 (s, 1H), 8.36 (d, J = 7.6Hz, 1H), 8.26 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz,2H), 7.66 (d, J = 8.4 Hz, 2H), 5.01- 4.96 (m, 1H), 4.82- 4.68 (m, 6H),3.22 (q, J = 7.2 Hz, 2H), 2.52-2.48 (m, 1H), 1.23-1.19 (m, 6H), 0.47 (d,J = 6.8 Hz, 3H). 41

552.1 (M + H)+ (CD₃OD) δ 9.09 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 1.2 Hz,,1H), 7.91 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 5.14 (d, J =14.4 Hz, 1H), 4.74 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 3.22 (q, J = 7.6Hz, 2H), 2.54-2.52 (m, 1H), 2.22-2.19 (m, 2H), 1.83-1.60 (m, 8H), 1.33(d, J = 6.8 Hz, 4H), 1.22 (d, J = 7.2 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H).42

520.6 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.29, (s, 1H), 7.90 (d, J = 7.6Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 5.16 (d, J = 14.4 Hz, 1H), 4.73 (d, J= 14.4 Hz, 1H), 4.72 (s, 2H), 3.41 (m, 1H), 3.20 (q, J = 7.2 Hz, 2H),2.58- 2.47 (m, 1H), 2.20- 2.06 (m, 3H), 2.05- 1.95 (m, 4H), 1.92- 1.82(m, 2H), 1.58- 1.41 (m, 2H), 1.32 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H). 43

521.5 (M + H)+ (CD₃OD) δ 9.12 (s, 1H), 9.00, (d, J = 2.0 Hz, 1H), 8.32(s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 5.17 (d, J= 15.6 Hz, 1H), 4.83 (s, 2H), 4.74 (d, J = 14.8 Hz, 1H), 3.46 (m, 1H),3.30 (q, J = 7.6 Hz, 2H), 2.60- 2.49 (m, 1H), 2.20- 2.06 (m, 3H), 2.05-1.95 (m, 4H), 1.92- 1.82 (m, 2H), 1.58- 1.41 (m, 2H), 1.33 (d, J = 6.8Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H). 44

542.1 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.28 (s, 1H), 7.90 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 5.16-5.05 (m, 1H), 4.72 (s, 3H), 3.68(s, 3H), 3.44- 3.29 (m, 2H), 3.21 (q, J = 7.6 Hz, 2H), 2.52-2.33 (m,2H), 2.13-1.83 (m, 6H), 1.57-1.44 (m, 2H), 1.31 (d, J = 6.4 Hz, 4H),1.21 (t, J = 7.6 Hz, 4H), 1.09 (d, J = 6.4 Hz, 3H). 45

514.2 (M + H)+ (CD₃OD) δ 9.42 (t, J = 6.0 Hz, 1H), 9.10 (s, 1H), 8.30(s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 5.13-5.08(m, 2H), 4.77-4.62 (m, 4H), 3.41-3.37 (m, 5H), 3.26-3.17 (m, 3H),2.56-2.48 (m, 2H), 2.21-2.13 (m, 2H), 2.03-1.92 (m, 3H), 1.32 (d, J =7.2 Hz, 3H), 1.28-1.19 (m, 6H), 1.10 (d, J = 6.8 Hz, 3H). 47

567.53 (M + H)+ (CD₃OD) δ 9.24 (d, J = 2.0 Hz, 1H), 8.99 (d, J = 1.6 Hz,1H), 8.55 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 2.4, 8.4 Hz, 1H), 7.69 (d,J = 8.4 Hz, 1H), 4.83 (s, 2H), 4.71 (d, J = 3.2 Hz, 1H), 3.88 (dd, J =9.2, 13.8 Hz, 1H), 3.30 (q, J = 7.6 Hz, 2H), 3.16 (dd, J = 5.2, 13.8 Hz,1H), 2.62-2.58 (m, 1H), 2.33-1.71 (m, 6H), 1.38 (d, J = 6.8 Hz, 3H),1.35-1.04 (m, 4H), 1.25 (t, J = 7.6 Hz, 3H), 0.53 (d, J = 6.8 Hz, 3H).48

531.1 (M + H)+ (CD₃OD) δ 9.01 (s, 1H), 8.21 (s, 1H), 7.86 (dd, J = 8.4,10.4 Hz, 4H), 7.76 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H),4.75-4.50 (m, 6H), 4.00-3.68 (m, 5H), 3.18 (q, J = 7.6 Hz, 2H),3.00-2.90 (m, 1H), 2.10-2.04 (m, 1H), 1.98-1.85 (m, 1H), 1.19 (t, J =7.6 Hz, 3H). 49

567.1 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.30 (s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 4.12-4.05 (m, 2H),3.65-3.60 (m, 2H), 3.50-3.40 (m, 2H), 3.30-3.25 (m, 5H), 3.20 (q, J =7.2 Hz, 2H), 2.60- 2.50 (m, 1H), 2.34- 2.20 (m, 3H), 1.82- 1.73 (m, 2H),1.32 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 1.15-1.00 (m, 3H).50

531.1 (M + H)+ (CD₃OD) δ 8.98 (s, 1H), 8.17 (s, 1H), 7.85 (dd, J = 8.4,14.4 Hz, 4H), 7.76 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H),4.80-4.40 (m, 6H), 4.00-3.65 (m, 5H), 3.18 (q, J = 7.6 Hz, 2H),3.00-2.88 (m, 1H), 2.25-2.13 (m, 1H), 2.13-2.00 (m, 1H), 1.19 (t, J =7.6 Hz, 3H). 51

531.1 (M + H)+ (CD₃OD) δ 9.00 (s, 1H), 8.19 (s, 1H), 7.84 (t, J = 8.0Hz, 4H), 7.78 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 4.80-4.45(m, 6H), 4.00-3.65 (m, 5H), 3.18 (q, J = 7.6 Hz, 2H), 3.00-2.88 (m, 1H),2.27-2.13 (m, 1H), 2.10-1.98 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H). 52

531.1 (M + H)+ (CD₃OD) δ 8.99 (s, 1H), 8.19 (s, 1H), 7.85 (dd, J = 8.0,17.6 Hz, 4H), 7.80-7.70 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 4.70- 4.35(m, 6H), 3.95- 3.65 (m, 5H), 3.18 (q, J = 7.6 Hz, 2H), 3.00-2.88 (m,1H), 2.12-2.06 (m, 1H), 2.00-1.87 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H). 53

553.1 (M + H)+ (CD₃OD) δ 9.12 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H),8.36-8.32 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 5.16 (d, J = 15.6 Hz, 1H),4.89-4.87 (m, 2H), 4.73 (d, J = 15.2 Hz, 1H), 3.42- 3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58- 2.51 (m, 1H), 2.20- 1.90 (m, 6H) 1.50- 1.39 (m, 2H),1.33 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.24-1.20 (m, 2H),1.10 (d, J = 6.8 Hz, 3H). 54

559.50 (M + H)+ (CD₃OD) δ 9.11 (s, 1H), 9.01 (s, 1H), 8.35 (dd, J = 2.0,8.4 Hz, 1H), 8.31 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 1.2Hz, 1H), 7.50 (dd, J = 1.6, 8.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.01(d, J = 15.6 Hz, 1H), 4.84 (s, 2H), 4.68 (dd, J = 12.8, 24.0 Hz, 2H),3.34 (s, 2H), 3.30 (q, J = 7.6 Hz, 2H), 2.38 (broad s, 1H), 1.25 (t, J =7.6 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 55

552.7 (M + H)+ (CD₃OD) δ 8.60 (s, 1H), 8.33 (s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 4.95 (m, 1H), 4.62 (m, 4H), 3.89 (s,2H), 3.21 (q, J = 7.2 Hz, 2H), 2.48-2.38 (m, 1H), 2.24-2.12 (m, 1H),2.11-1.86 (m, 5H), 1.48-1.38 (m, 2H), 1.37-1.24 (m, 2H), 1.29 (d, J =6.8 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H). 56

512.8 (M + H)+ (CD₃OD) δ 8.69 (s, 1H), 8.31 (s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.8 Hz, 4H), 7.52 (d, J = 8.8 Hz, 2H), 4.95 (d, J= 15.6 Hz, 1H), 4.72 (m, 2H), 4.66 (d, J = 14.4 Hz, 1H), 4.54 (d, J =12.8 Hz, 1H), 3.90 (s, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.38-2.23 (m, 1H),1.22 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 6.8 Hz,3H). 57

503.7 (M + H)+ (CD₃OD) δ 8.66 (s, 1H), 8.30 (s, 1H), 7.90-7.82 (m, 6H),7.65-7.56 (m, 2H), 4.94 (d, J = 15.6 Hz, 1H), 4.71 (m, 2H), 4.64 (m,2H), 3.90 (s, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.39-2.27 (m, 1H), 1.22 (t,J = 7.2 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 58

546.5 (M + H)+ (CD₃OD) δ 8.67 (s, 1H), 8.31 (s, 1H), 7.90-7.81 (m, 6H),7.67-7.56 (m, 2H), 4.95 (d, J = 15.6 Hz, 1H), 4.73 (m, 3H), 4.65 (m,1H), 3.90 (s, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.38-2.25 (m, 1H), 1.22 (t,J = 7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 59

561.1 (M + H)+ (CD3OD) δ 9.11 (d, J = 1.6 Hz, 1H), 9.03 (d, J = 2.0 Hz,1H), 8.36-8.25 (m, 2H), 7.89 (dd, J = 8.0, 24.0 Hz, 4H), 7.78 (d, J =8.4 Hz, 1H), 5.38 (q, J = 7.2 Hz, 1H), 5.08- 5.03 (m, 1H), 4.85- 4.65(m, 4H), 3.32- 3.29 (m, 2H), 2.40- 2.35 (m, 1H), 1.68 (d, J = 7.2 Hz,3H), 1.28 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 0.90 (d, J =6.8 Hz, 3H). 60

561.1 (M + H)+ (CD3OD) δ 9.12 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 1.6 Hz,1H), 8.35-8.25 (m, 2H), 7.88 (q, J = 8.0 Hz, 4H), 7.75 (d, J = 8.0 Hz,1H), 5.38 (q, J = 7.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.85-4.71 (m, 4H),3.31-3.28 (m, 2H), 2.45-2.35 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.28 (t,J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). 61

510.5 (M + H)+ 62

524.5 (M + H)+ 63

539.5 (M + H)+ 64

479.5 (M + H)+ 66

547.7 (M + H)+ 67

547.5 (M + H)+ 68

533.6 (M + H)+ 69

495.6 (M + H)+ 70

522.6 (M + H)+ 71

532.6 (M + H)+ 72

526.6 (M + H)+ 73

458.5 (M + H)+ 74

547.7 (M + H)+ 75

518.6 (M + H)+ 76

458.53 (M + H)+ 77

477.55 (M + H)+ 78

455.41 (M + H)+ 79

489.55 (M + H)+ 80

528.56 (M + H)+ 81

566.46 (M + H)+ 82

458.5 (M + H)+ 83

456.49 (M + H)+ 84

456.49 (M + H)+ 85

464.45 (M + H)+ 86

484.5 (M + H)+ 87

510.5 (M + H)+ 88

554.7 (M + H)+ 89

524.6 (M + H)+ 90

476.6 (M + H)+ 91

546.6 (M + H)+ 92

512.6 (M + H)+ 93

621.6 (M + H)+ 94

485.5 (M + H)+ 95

561.6 (M + H)+ 96

472.51 (M + H)+ 97

469.55 (M + H)+ 98

541.66 (M + H)+ 99

490.59 (M + H)+ 100

475.57 (M + H)+ 101

485.45 (M + H)+ 102

539.5 (M + H)+ 103

539.5 (M + H)+ 104

525.5 (M + H)+ 105

491.5 (M + H)+ 106

539.5 (M + H)+ 107

505.6 (M + H)+ 108

517.6 (M + H)+ 109

553.5 (M + H)+ 110

519.6 (M + H)+ 111

554.5 (M + H)+ 112

533.6 (M + H)+ 113

519.6 (M + H)+ 114

503.6 (M + H)+ 115

455.5 (M + H)+ 116

532.5 (M + H)+ 117

446.4 (M + H)+ 118

534.5 (M + H)+ 119

546.5 (M + H)+ 120

482.5 (M + H)+ 121

557.5 (M + H)+ 122

406.4 (M + H)+ 123

562.4 (M + H)+ 124

428.4 (M + H)+ 125

496.5 (M + H)+ 126

544.6 (M + H)+ 127

532.6 (M + H)+ 128

604.5 (M + H)+ 129

485.6 (M + H)+ 130

496.5 (M + H)+ 131

496.5 (M + H)+ 132

496.5 (M + H)+ 133

536.46 (M + H)+ (CD₃OD) δ 9.02 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.90(s, 1H), 7.82 (m, 4H), 4.96 (d, J = 16.0 Hz, 1H), 4.91 (m, 2H), 4.78 (s,2H), 4.52 (s, 2H), 3.58 (q, J = 7.6 Hz, 2H), 2.38 (m, 1H), 1.21 (t, J =7.6 Hz, 3H), 1.17 (d, J = 8.0 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). 134

520.56 (M + H)+ 135

593.61 (M + H)+ 136

579.47 (M + H)+ 137

532.62 (M + H)+ 138

530.5 (M + H)+ 139

518.5 (M + H)+ 140

590.5 (M + H)+ 141

574.50 (M + H)+ (CD₃OD) δ 9.12 (s, 1H), 8.90 (s, 1H), 8.32 (s, 1H), 8.17(d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H),7.65 (d, J = 8.4 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H), 4.77 (dd, J = 13.2,30.0 Hz, 2H), 3.34 (s, 2H), 3.26 (q, J = 7.6 Hz, 2H), 2.37 (broad s,1H), 1.84 (dd, J = 4.4, 7.6 Hz, 2H), 1.52 (dd, J = 4.4, 7.6 Hz, 2H),1.23 (t, J = 7.6 Hz, 3H), 1.16 (d, J = 6.0, 3H), 0.89 (d, J = 6.8 Hz,3H). 142

561.55 (M + H)+ (CD₃OD) δ 9.11 (s, 1H), 8.87 (s, 1H), 8.33 (d, J = 8.0Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 5.04 (d, J= 15.6 Hz, 1H), 4.89-4.82 (m, 2H), 4.87 (s, 2H), 4.76 (dd, J = 13.2,28.8 Hz, 2H), 3.33 (q, J = 7.6 Hz, 2H), 2.58 (s, 3H), 2.36 (bs, 1H),1.26 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H), 0.88 (d, J = 6.8 Hz,3H). 143

561.52 (M + H)+ (CD₃OD) δ 9.12 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 8.35(s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.83 (d, J= 8.0 Hz, 2H), 5.07 (d, J = 15.2 Hz, 1H), 4.91- 4.71 (m, 4H), 4.77 (dd,J = 12.4, 35.4 Hz, 2H), 3.41 (q, J = 7.6 Hz, 2H), 3.06 (s, 3H), 2.36(broad s, 1H), 1.28 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 5.2 Hz, 3H), 0.88(d, J = 6.8 Hz, 3H). 144

565.51 (M + H)+ (CD₃OD) δ 9.08 (s, 1H), 8.81 (s, 1H), 8.28 (s, 1H), 8.12(d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H),5.04 (d, J = 14.4 Hz, 1H), 4.91- 4.70 (m, 2H), 4.88 (s, 2H), 4.76 (dd, J= 12.4, 33.4 Hz, 2H), 3.33 (q, J = 7.6 Hz, 2H), 2.35 (broad s, 1H), 1.25(t, J = 7.6 Hz, 3H), 1.13 (d, J = 5.2 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).145

518.55 (M + H)+ 146

506.58 (M + H)+ 148

504.6 (M + H)+ 149

509.5 (M + H)+ 150

513.6 (M + H)+ 151

499.6 (M + H)+ 152

525.6 (M + H)+ 153

511.5 (M + H)+ 154

525.5 (M + H)+ 155

480.5 (M + H)+ 156

577.5 (M + H)+ 157

561.6 (M + H)+ 158

509.5 (M + H)+ 159

548.1 (M + H)+ (CD₃OD) δ 9.13 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 3.2 Hz,1H), 8.29 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.92-7.85 (m, 4H),5.10-5.04 (m, 3H), 4.89-4.85 (m, 1H), 4.80-4.76 (m, 3H), 3.60 (q, J =7.2 Hz, 2H), 2.42- 2.38 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.17 (d, J =6.8 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H). Cmpd General No. StartingMaterial Method 3

A 4

A 5

A 7

A 8

C 10

C 11

F 12 Reduction of 10 14 Oxidation of 12 followed by methyl Grignardaddition 17

A 18

A 19

A 20

B 21

A 22

A 23

A 24

A 25

E 26

A 27

B 28

A 29

A 30

A 31

A 32

F 33

A 34

A 35

A 36

A 37

A 38

B 39

A 40

A 41

B 42

B 43

B 44

B 45

B 47

F 48

A 49

B 50

A 51

A 52

A 53

B 54

A 55

B 56

A 57

A 58

A 59

A 60

A 61

G 62

G 63

G 64

G 66

G 67

G 68

G 69

G 70

G 71

G 72

G 73

G 74

G 75

G 76

G 77

G 78

G 79

G 80

G 81

G 82

G 83

G 84

G 85

G 86

G 87

G 88

G 89

G 90

G 91

G 92

G 93

G 94

G 95

G 96

G 97

G 98

G 99

G 100

G 101

G 102

G 103

G 104

G 105

G 106

G 107

G 108

G 109

G 110

G 111

G 112

G 113

G 114

G 115

G 116

G 117

G 118

G 119

G 120

G 121

G 122

G 123

G 124

G 125

G 126

G 127

G 128

G 129

G 130

G 131

G 132

G 133

G 134

G 135

G 136 135 H 137

G 138 126 H 139 127 H 140 128 H 141

G 142

G 143

G 144

G 145 137 H 146 134 H 148 127 H 149

G 150

G 151 150 H 152

G 153

G 154

G 155

G 156

G 157

G 158

G 159

G

BIOLOGICAL ASSAYS

Radio-Ligand ROR

Binding Assay (Assay 1)

Compounds of the present invention were tested for ability to bind toROR

in a cell-free competition assay with commercially availableradio-ligand (RL), 25-hydroxy [26,27-³H]-cholesterol (PerkinElmer, Cat.# NET674250UC), for a ligand binding site on a recombinant ROR

Ligand Binding Domain (LBD) protein expressed as a6×His-Glutathione-S-Transferase (GST) fusion. The assay was performed in96-well SPA plates (PerkinElmer, Cat. #1450-401) in 50 mM HEPES buffer,pH 7.4, containing 150 mM NaCl, 5 mM MgCl₂, 10% (v/v) glycerol, 2 mMCHAPS, 0.5 mM β-octylglucopyranoside and 5 mM DTT. Tested compounds weredissolved in DMSO, and semi-log (3.162×) serial dilutions of thecompounds were prepared in the same solvent. Two μL of the DMSOsolutions were mixed with 28 μL of 8.6 nM 25-hydroxy[26,27-³H]-cholesterol and 50 μL of 24 nM ROR

LBD. The plate was shaken at 700 rpm for 20 min and incubated for 10 minat rt, after which 40 μL of poly-Lys YSi SPA beads (PerkinElmer, Cat. #RPNQ0010) were added to achieve 50 μg of the beads per well. The platewas incubated on an orbital shaker for 20 min and then for 10 minwithout agitation at rt. SPA signal for tritium beta radiation wasregistered on PerkinElmer Microbeta plate reader. Percent inhibitionvalues were calculated based on the high signal obtained with DMSOcontrol and the low signal observed with 10 μM standard ROR

inverse agonist T0901317 (SigmaAldrich, Cat. # T2320). The percentinhibition vs. concentration data were fit into a four-parameter model,and IC50 values were calculated from the fit as the concentrationscorresponding to the inflection points on the dose-response curves.Inhibitory constants (Ki) were calculated using the following equation,where [RL] is the concentration in the assay and K_(D) is a dissociationconstant of 25-hydroxy [26,27-³H]-cholesterol:

$K_{i} = {\frac{{IC}_{50}}{\left( {1 + \frac{\lbrack{RL}\rbrack}{K_{D}}} \right)}.}$

ROR

t 5×RORE Assay in Jurkat Cells (Assay 2)

Compounds of the present invention were tested for ROR

inverse agonist activity in a cell-based, transcriptional activityassay. Secreted Nanoluc® luciferase was used as a reporter fortranscriptional activity of the full-length ROR

t in Jurkat cells (ATCC, Cat. # TIB-152). A reporter plasmid wasconstructed by inserting 5 repeats of the ROR Response Element (RORE)AAAGTAGGTCA (SEQ ID NO:1) into a commercially available promoterlessplasmid pNL1.3[secNluc] (Promega, Cat. # N1021) using KpnI and HindIIIrestriction sites. The expression plasmid for ROR

t was purchased (Geneocopoeia, Cat. # EX-T6988-M02). Jurkat cells (30million cells) were transfected with 11 μg of EX-T6988-M02 and 26 μg ofthe reporter plasmid in OptiMEM® media using Lipofectamine® LTX andPlus™ reagents (Life Technologies, Cat. #15338-100). After 5-6 hrs ofincubation at 37° C./5% CO₂, the cells were collected, resuspended inphenol-red free RPMI media containing 10% (v/v) delipidated FBS(Hyclone, Cat. # SH30855.03) and dispensed into 96-well clear bottomtissue culture plates (CoStar, Cat. #3603), at 80,000 cells per well.Tested compounds were added to the cells in the same media (finalconcentration of DMSO was 0.1% (v/v)), and the plates were incubated at37° C./5% CO₂ for 16-18 hrs. Luciferase activity in the conditionedsupernatants was determined with NanoGlo® assay reagents (Promega, Cat.#N1130). Percent inhibition values were calculated based on the fullyinhibited and non-inhibited (DMSO) controls, and the values wereregressed against concentrations of the tested compounds to derive IC50values using a four-parameter non-linear fitting model.

The results of assays 1 and 2 are shown in Table 2.

TABLE 2 RORγ Binding RORγt5X Ki IC50 Range* Range* Compound # (nM) (nM)1 +++ +++ 2 +++ +++ 3 +++ +++ 4 +++ +++ 5 +++ +++ 6 +++ + 7 +++ ++ 8+++ + 9 +++ ++ 10 +++ + 11 ++ + 12 ++ + 13 + 14 ++ 15 +++ + 16 ++ 17 ++++++ 18 + 19 + 20 +++ +++ 21 ++ ++ 22 +++ +++ 23 ++ 24 +++ + 25 +++ + 26++ 27 +++ ++ 28 +++ +++ 29 +++ +++ 30 +++ +++ 31 +++ +++ 32 +++ ++ 33+++ +++ 34 +++ +++ 35 +++ ++ 36 ++ 37 + 38 +++ ++ 39 +++ +++ 40 ++ 41+++ + 42 +++ + 43 +++ + 44 +++ ++ 45 +++ +++ 46 +++ + 47 +++ ++ 48 + +49 +++ +++ 50 + + 51 ++ ++ 52 ++ ++ 53 ++ 54 +++ +++ 55 +++ +++ 56 +++++ 57 +++ +++ 58 +++ +++ 59 +++ +++ 60 ++ 61 + 62 + 63 +++ ++ 64 +++ ++65 ++ 66 + 67 +++ +++ 68 + 69 + 70 + 71 ++ 72 ++ 73 + 74 + 75 + 76 ++77 + 78 ++ 79 + 80 + 81 + 82 + 83 ++ 84 + 85 + 86 + 87 + 88 + 89 ++ 90++ 91 ++ 92 + 93 + 94 + 95 ++ 96 + 97 + 98 + 99 + 100 + 101 + 102 ++103 + 104 ++ 105 + 106 ++ 107 ++ 108 + 109 +++ + 110 + 111 ++ 112 + 113++ 114 + 115 ++ 116 ++ 117 + 118 + 119 + 120 + 121 + 122 + 123 ++ 124 +125 + 126 + 127 ++ 128 ++ 129 ++ 130 + 131 ++ 132 ++ 133 +++ ++ 134 +135 + 136 + 137 + 138 + 139 +++ ++ 140 + 141 +++ +++ 142 +++ +++ 143 +++++ 144 +++ +++ 145 + 146 + 147 ++ 148 + 149 +++ ++ 150 + 151 ++ 152 +153 + 154 + 155 ++ + 156 + 157 + 158 ++ 159 +++ ++ *+ means >1000 nM; ++means 100 nM-1000 nM; +++ means <100 nM.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

1-24. (canceled)
 25. A method of treating dry eye comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound having the Formula (III):

or a pharmaceutically acceptable salt thereof, wherein R² and R³ areeach independently hydrogen, hydroxy, monocyclic cycloalkyl, monocyclicheterocyclyl, or (C₁-C₆)alkyl, wherein the (C₁-C₆)alkyl is optionallysubstituted with 1 to 2 groups independently selected from hydroxy,halo, and cyano; R⁴ is hydrogen, (C₁-C₃)alkyl, or ═O; X is —C(O)NH— or—NHC(O)—; m is 0, 1, or 2; n is 0, 1, 2, or 3; Cy¹ is absent or isselected from (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, aryl, heteroaryl,heterocyclyl, and cycloalkyl, wherein the aryl, heteroaryl,heterocyclyl, and cycloalkyl are each optionally substituted with 1 to 3groups independently selected from R⁵; Cy² is absent or is selected from(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₃)alkoxycarbonyl,halophenyl(C₁-C₃)alkoxycarbonyl, aryl, heteroaryl, monocycliccycloalkyl, and monocyclic heterocyclyl, wherein the aryl, heteroaryl,monocyclic cycloalkyl, and moncyclic heterocyclyl are each optionallysubstituted with 1 to 3 groups independently selected from R⁶; and R⁵and R⁶ are each independently selected from halo, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, heterocyclyl, hydroxy(C₁-C₆)alkyl, CO₂H,(CH₂)₁₋₃COOH, (C₁-C₃)alkylcarbonyloxy, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkylsulfinyl, (C₃-C₆)cycloalkylsulfinyl,(C₄-C₇)cycloalkylalkylsulfinyl, halo(C₁-C₆)alkylsulfonyl,halo(C₃-C₆)cycloalkylsulfinyl, halo(C₄-C₇)cycloalkylalkylsulfinyl,(C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl,(C₄-C₇)cycloalkylalkylsulfonyl, halo(C₁-C₆)alkylsulfonyl,halo(C₃-C₆)cycloalkylsulfonyl, halo(C₄-C₇)cycloalkylalkylsulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkyl-carbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, aryl, heteroaryl,oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, hydroxy(C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylhydroxycarbonyl, (C₁-C₆)alkylhydroxy(C₁-C₆)alkyl,(C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl,[(C₁-C₆)alkyl(C₄-C₆)heterocyclyl](C₁-C₆)alkyl, anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl.
 26. The method of claim25, wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof.
 27. The method of claim26, wherein the compound is of Formula (V) or (VI):

or a pharmaceutically acceptable salt thereof.
 28. The method of claim27, wherein the compound is of Formula (VII):

or a pharmaceutically acceptable salt thereof.
 29. The method of claim28, wherein R² and R³ are each independently hydrogen, hydroxy, or(C₁-C₃)alkyl.
 30. The method of claim 29, wherein Cy² is present and isselected from aryl, heteroaryl, monocyclic cycloalkyl, and monocyclicheterocyclyl, each of which is optionally substituted with 1 to 2 groupsindependently selected from R⁶.
 31. The method of claim 30, wherein Cy²is phenyl, pyrimidinyl, cyclohexyl, or pyridinyl, each of which areoptionally substituted with 1 to 2 groups independently selected fromR⁶.
 32. The method of claim 31, wherein Cy¹ is phenyl, piperidinyl,tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl, piperazinyl,azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl, pyridazinyl,pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl,1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, orimidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with1 to 2 groups independently selected from R⁵.
 33. The method of claim32, wherein Cy¹ is phenyl, piperidinyl, tetrahydro-2H-thiopyranyl1,1-dioxide, pyridinyl, piperazinyl, azetidinyl, imidazolyl,tetrahydropyranyl, 1,4-dioxanyl, pyridazinyl, pyrazolyl, pyrrolidinyl,cyclohexyl, morpholinyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl,1,2,3,4-tetrahydro-1,8-naphthyridinyl, 2,3-dihydro-1H-indenyl, orimidazo[1,2-a]pyrimidinyl, each of which is optionally substituted with1 to 2 groups independently selected from R⁵, wherein at least one R⁵ is(C₁-C₃)alkylsulfonyl or (C₁-C₃)alkylaminosulfonyl.
 34. The method ofclaim 33, wherein R² is (C₁-C₃)alkyl; n is 1 or 2; and Cy¹ is phenyl,pyridinyl, or piperidinyl, each of which is optionally substituted with1 to 2 groups independently selected from R⁵, wherein at least one R⁵ is(C₁-C₃)alkylsulfonyl or (C₁-C₃)alkylaminosulfonyl.
 35. The method ofclaim 34, wherein Cy² is cyclohexyl optionally substituted with 1 to 2groups independently selected from R⁶.
 36. The method of claim 35,wherein R⁵ is selected from halo, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, cyano,hydroxy(C₁-C₃)alkyl, (C₁-C₃)alkoxycarbonyl, (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, oxo, hydroxy, (C₁-C₃)alkylcarbonyl,hydroxy(C₁-C₃)alkylcarbonyl, (C₁-C₃)alkylhydroxycarbonyl,(C₁-C₃)alkylaminosulfonyl, (C₁-C₃)alkylaminocarbonyl,di(C₁-C₃)alkylamino(C₂-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,[(C₁-C₃)alkyl(C₄-C₆)heterocyclyl](C₁-C₃)alkyl, and(C₁-C₃)alkylhydroxy(C₁-C₃)alkyl; and R⁶ is selected from halo,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, cyano, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxycarbonyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkoxy,halo(C₁-C₃)alkoxy, oxo, hydroxy, aryl(C₁-C₃)alkoxycarbonyl,(C₁-C₃)alkylhydroxy(C₁-C₃)alkyl, heteroaryl, and (C₁-C₃)alkoxycarbonyl.37. The method of claim 36, wherein R⁵ is selected from halo,(C₁-C₃)alkoxy, hydroxy, (C₁-C₃)alkyl, hydroxy(C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₆)alkoxycarbonyl,di(C₁-C₃)alkylamino(C₂-C₆)alkoxy,[(C₁-C₃)alkyl(C₄-C₆)heterocyclyl](C₁-C₃)alkyl, oxo,(C₁-C₃)alkylcarbonyl, (C₁-C₃)alkylaminosulfonyl, (C₁-C₃)alkylsulfonyl,and cyano; and R⁶ is selected from halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy,halo, cyano, (C₁-C₃)alkoxycarbonyl, (C₁-C₃)alkylhydroxy(C₁-C₃)alkyl,2-methyl-2H-tetrazolyl, hydroxy(C₁-C₃)alkyl, and halo(C₁-C₃)alkoxy. 38.The method of claim 37, wherein R⁵ is selected from halo, cyano,(C₁-C₃)alkyl, (C₁-C₃)alkylaminosulfonyl, and (C₁-C₃)alkylsulfonyl; andR⁶ is selected from halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo, cyano,(C₁-C₃)alkoxycarbonyl, 2-methyl-2H-tetrazolyl, and halo(C₁-C₃)alkoxy.39. The method of claim 38, wherein Cy¹ is

R¹⁰ is (C₁-C₃)alkyl or (C₁-C₃)alkylamino; and Z is CH or N.
 40. Themethod of claim 39, wherein

R¹² is (C₁-C₃)alkoxycarbonyl, halo, dihalo, (C₁-C₃)alkoxy, orhalo(C₁-C₃)alkyl; R¹³ is halo or halo(C₁-C₃)alkyl; and R¹⁴ is halo,cyano, halo(C₁-C₃)alkyl, halo(C₁-C₃)alkoxy, or 2-methyl-2H-tetrazolyl.41. The method of claim 40, wherein R¹² to R¹⁴ are each CF₃.
 42. Themethod of claim 41, wherein R² is isopropyl.
 43. The method of claim 25,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 44. A method of treatingdry eye comprising administering to a subject in need thereof atherapeutically effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof.